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Major Diseases Research Catalogue of Research Projects (2003-2005) in the Sixth Framework Programme
PROJECT SYNOPSES
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EUROPEAN COMMISSION
Major Diseases Research

Catalogue of Research Projects (2003-2005)
in the Sixth Framework Programme
Edited by Alain Vanvossel

2005 Life Sciences, Genomics and Biotechnology for Health
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Table of contents
Foreword 7
Introduction 9
Overarching projects 11
Eicosanox 12
ECRIN-RKP 14
Cardiovascular 17
Bloodomics 18
EVGN 20
MOLSTROKE 24
EuroClot 26
Myocardial Repair 28
Diabetes 31
Diabesity 32
EXGENESIS 34
EUGENE2 36
TONECA 39
IMMIDIAB 41
Rare diseases 43
Eumitocombat 44
Euroglycanet 47
GENESKIN 49
EuroWilson 52
PWS 56
EUGINDAT 58
EURAPS 60
AUTOROME 62
Orphanplatform 64
Major Diseases Research (2003-2005)

3
Anti-Microbial Drug Resistance 67

EUR-INTAFAR 68
ActinoGEN 70
VIRGIL 73
PNEUMOPEP 75
AMIS 77
PREVIS 79
COBRA 82
micro-MATRIX 85
Brain, neurological and psychiatric diseases 87

PROMEMORIA 88
NEWMOOD 90
APOPIS 93
GENADDICT 95
EUROSCA 97
NeuroNE 100
BrainNetEurope II 102
AUTISM MOLGEN 106
SYNSCAFF 108
EUROHEAD 111
SPASTICMODELS 113
NCL-models 116
NEUROKCNQPATHIES 118
X-ALD 120
PainGenes 122
GRIPANNT 124
STRESSPROTECT 126
INTERDEVO 129
NeuroDisseminator 131
EUROMEMO 132
ESNI course 2003 135
FENS Forum 2004 137
RABRE 139
Human development and ageing 141

MIMAGE 142
GEHA 144
EMBIC 146
Cells into Organs 148

4
LINK-AGE 150
ANABONOS 152
OSTEOGENE 154
AGEACTION 156
Cancer 159
INTACT 162
BIOCARE 164
Angiotargeting 166
PRIMA 168
Active p53 170
EMIL 173
TRANSFOG 176
FIRST 179
CANCERDEGRADOME 182
STROMA 185
Mutp53 187
MOL CANCER MED 191
EUROXY 194
MAESTRO 195
CCPRB 196
eTUMOUR 198
TRANSBIG 200
European LeukaemiaNet 202
DNA METHYLATION 206
European MCL Network 209
BRECOSM 212
MetaBre 214
ENACT 217
PROTHETS 219
P-MARK 221
EUSTIR 223
EUROCAN +PLUS 225
Indexes 227
Index by acronym 228
Index by contract number 230
Index by project coordinator 232

5
Foreword
Millions of European citizens battle with chronic diseases every day. The ultimate
objective of any health research funding is to eliminate such diseases. The task is
huge - major diseases,such as cardiovascular,brain diseases and cancer,are immensely
complex and can often only be tackled by multidisciplinary teams from different
countries.For over a quarter of a century,European Union Framework Programmes
have supported research in life sciences,providing opportunities for research funding
and the training of scientists. Europe is fortunate to have excellent research centres
active in these fields the challenge is to ensure their further development and to
facilitate the creation of effective and durable partnerships between them.
The current Sixth Framework Programme focuses on major diseases as part of its first thematic priority 'Life
sciences, genomics and biotechnology for health', with an emphasis on the field of genomics which has ushered
in a new era in medical research.
This publication illustrates the EU's essential commitment to major disease research, featuring the 87 projects
supported under the first and second calls for proposals in the actual Framework Programme, representing a
global budgetary effort of about 380 million.
Let us not underestimate this collaborative research effort, bringing together the best teams in Europe in basic
research,molecular biology,clinical expertise,epidemiology and bioinformatics.It must be recognised that,through
the research Framework Programmes,the EU has the largest experience in the world thanks to such multinational
and multidisciplinary co-operation which is essential because of the scale of the problems faced. These multi-
skilled approaches are needed to generate important advances in our scientific knowledge and ultimately to lead
us towards new drugs, therapies and treatments for the benefit of the patients and for public health in general.
Research must become embedded in healthcare. As sure as research delivers solutions to some problems, it also
opens up further questions.The current work being funded should also help to point us in the right direction as
we prepare for the Seventh Framework Programme, now expected to embrace even broader ambitions and
objectives for co-operation in health research. As Commissioner for Research, I am convinced that increased
support in (health) research is a key element for Europe's industrial growth and a cornerstone of the knowledge
based economy and society.
Janez Potocnik

7
Introduction
The current Sixth Framework Programme (FP6 2002-
2006) is dedicating around 800 million to supporting
research in the area of 'Combating major diseases:
application-orientated genomic approaches to
medical knowledge and technologies' with the aim of improving years and increases the risk of cardiovascular disease by two to four
patient health and quality of life in Europe and around the world. times. Projects funded under the first two FP6 calls for proposals are
tackling the prediction of type 1 diabetes while, with respect to type
Under FP6,five possible funding instruments provide support to larger
2 diabetes (TP2D), projects are addressing the treatment of obesity,
or smaller projects with different objectives. Integrated Projects (IP)
the effects of exercise and the genetics of TP2D in migrant population.
and Specific Targeted Research Projects (STREP) are aimed at
generating, demonstrating and validating new knowledge through 'Rare diseases' (RDs), by definition, affect only small groups of people.
research and development. Networks of Excellence (NoE) support In Europe, RDs are defined as those affecting less than one person in
strategic research coordination through extensive networking. 2 000.These conditions are often genetic in nature, usually severely
Coordination Actions (CA) and Specific Support Actions (SSA) debilitating and life-threatening.Their low prevalence,the only feature
promote collaboration and coordination of smaller scale projects,and shared by all RDs, confirms the undeniable added value of teamwork
other activities such as conferences and studies. and pooling of resources and patient data at the European level. Rare
diseases and disorders covered by the first two calls include disorders
Collaboration between industry and academia is strongly encouraged.
of mitochondrial oxidative phosphorylation, glycosylation and plasma
Emphasis is placed on the participation of small and medium-sized
membrane amino acids transporters; rare skin diseases; Wilson's
enterprises (SMEs) in all FP6 initiatives, including this part of the
disease; Prader-Willi syndrome; and autoimmune diseases. Some
programme, in recognition of their important and proven innovative
projects take a broad approach,addressing personalised medicine and
potential.
plan for the coordination of early clinical trials.
This catalogue features 87 projects selected under the first and second
Over time, bacteria, viruses, and other microscopic predators mutate
FP6 calls for proposals, presented by scientific area, for a total
into new strains resistant to existing medications. The problem of
contribution of about 380 million provided by the EU.
resistance to antimicrobials has grown into a major health concern
Several excellent projects have incorporated innovative post-genomic and now threatens to impede advanced medical interventions as well
and proteomics approaches.They are identifying genes,collecting data as treatment of common infections. Mortality due to drug resistance
and applying innovative bioinformatics techniques including the use has increased, while costs for medical care due to treatment failures
of model organisms to elucidate cellular and molecular mechanisms, have escalated. Some of the major aspects of this problem have
and to elaborate clinical aspects of diseases with a strong potential already been addressed in the first two calls through projects focusing
for new diagnostics. on the design of new antibiotics (addressing new molecular targets)
and new alternative treatment approaches (addressing virulence
This part of the FP6 thematic priority 'Life sciences, genomics and
factors and stimulating the immune response), improved
biotechnology for health' (TP1) covers a large spectrum of major
understanding of the molecular mechanisms behind antibiotic
diseases and, as such, supports research to combat cardiovascular
resistance, and the establishment of a vigilance network to control
diseases, diabetes and rare diseases; tackles the problem of anti-
and predict the development of antiviral drug resistance.
microbial drug resistance; studies the brain and neurological and
psychiatric diseases; enhances knowledge about molecular The brain may well be the most complex organ in the human body.
mechanisms of human development and healthy ageing; and finally, One-third of our genes and proteins are specific to the brain alone,
combats cancer. providing the basis for our unique intellectual capabilities.The more
we understand about how the brain works, the more we can unravel
Cardiovascular diseases claim more lives in Europe than any other
the causes of the many devastating neurological and psychiatric
medical condition.The World Health Organisation estimates that they
disorders and diseases, and try to find new treatments or even cures.
cause some 30% of mortality worldwide.Despite the growing number
Neurodegenerative diseases have been tackled on a broad scale under
of interventional and pharmacological approaches, much remains to
the first two calls for proposals.
be done. Some of the main aspects of cardiovascular diseases have
already been addressed by the first two FP6 calls for proposals,namely Two large initiatives, an IP and a NoE, are addressing all related
coronary artery disease, vascular diseases, atherothrombosis and disorders displaying abnormal protein aggregation, including
thrombotic stroke, heart failure, arrhythmias and myocardial repair. Alzheimer's, Parkinson's and Huntington's diseases, motor neurone
diseases and prion diseases.The NoE on 'Human brain tissue research'
Europe has seen an explosive increase in diabetes over the past two
is addressing brain banking. One project covers a rare genetic
decades.Today, an estimated 20 million people in the EU (about 4%
neurological disorder, spinocerebral ataxia, which causes progressive
of the population) suffer from this debilitating disease, excluding
movement disorders.
undiagnosed cases.This figure is expected to grow to at least 26 million
by 2030. Diabetes lowers the life expectancy of sufferers by up to 15

9
Important funded research projects in areas such as affective Acknowledgment

disorders, mechanisms of addiction or mechanisms of learning and
memory, migraine and pain in general, are now expected to generate This catalogue has been produced thanks to essential input from all
major impacts through the use of recently available genome data. project coordinators involved and the efficient co-operation of all
Other projects cover drug development related to cytoprotection members of Unit F2 'major diseases', in particular Catherine Berens,
and inhibition of stress. Philippe Cupers, Dambrauskaite Virginija, Mary Fitzgerald, Olaf Kelm,
Elengo Manoussaki, Elmar Nimmesgern, Jrgen Sautter, Nathalie
Growing old is a normal part of life, but it brings its own particular
Vercruysse, Jan Van de Loo, Maria Vidal, Christian Wimmer, all under
health challenges with it. The EU seeks to help Member States
the inspiring coordination of Thomas Jussen and Ludovica Serafini and
encourage good health for European citizens from the cradle to old
the guidance of Alain Vanvossel.
age as the ranks of the 'silver generation' grow, addressing their
specific medical needs will become ever more important.The area of
'human development and ageing' is meant to provide a strong
knowledge base for medical needs and good health throughout a
patient's lifetime.The study of healthy ageing has been addressed by
the first two FP6 calls, specifically with respect to genetic aspects and
the role of mitochondria. One NoE and one IP, addressing the
development of organs and embryo-implantation, respectively, tackle
questions of human development. Bone formation, anabolism and
osteoporosis are also covered.
Cancer is likely to remain one of the biggest killers of the beginning
of the 21st century. In Europe, almost 1 million people die of cancer
every year, and 2 million new cases of cancer are diagnosed. Cancer
is an elusive enemy. Its multiple causes including genetic
predisposition, environmental and life-style influences, infectious
agents and ageing and their complex interactions represent a major
challenge for basic and clinical research. So far, the budget allocated
specifically to the calls in the 'Combating cancer' section has enabled
the funding of 27 projects. A number of these focus on the analysis
of molecular targets, such as cell-cycle regulators, kinases,
phosphatases, telomerase, proteases, DNA repair molecules, p53
protein, and mitogen-activated protein kinase (MAPK) signalling, and
on molecular mechanisms surrounding angiogenesis, epigenetics
and hypoxia.
Research is also being funded on biomarkers for early detection,
prognosis and responsiveness to treatment.Moreover,therapies,such
as viral therapy, stem cell therapy, gene therapy, radiotherapy, novel
technologies, together with the development of new drugs, are being
covered by the funded projects. In addition, research on molecular
imaging is being supported by EU funding.There are also a number
of studies specific to particular types of cancer, such as leukaemia,
lymphoma, myeloid cell leukaemia, melanoma, colon cancer, breast
cancer, pancreatic cancer, prostate and childhood cancers.
Finally, one large IP has been funded on the topic of functional
genomics and proteomics of the pathways of nitric oxide and
eicosanoid signalling and their interactions.This initiative is overarching
several diseases, ultimately aiming to develop new therapies and
treatments for cardiovascular, cerebral and neoplastic diseases.
As can be seen from the catalogue, these 87 projects represent a
massive effort from the EU scientific community involved in life
sciences research for the ultimate benefit of both the patient and the
European citizen.

10
Overarching
projects
Eicosanox 12
ECRIN-RKP 14
OVERARCHING Eicosanox
PROJECTS
Eicosanoids and nitric oxide: Mediators of cardiovascular,

cerebral & neoplastic diseases
Summary Problem
The eicosanoids and nitric oxide (NO) are important signalling Eicosanoids and NO are involved in a number of severe endemic diseases
that plague the Western world, e.g.atherosclerosis,myocardial infarction,
molecules in many physiological and pathological processes, thrombosis, dementia and cancer. In fact, cardio- and cerebrovascular
including cardiovascular, cerebral and neoplastic disorders. disorders alone, such as coronary heart disease and stroke, are the
Together, these diseases account for the vast majority of deaths in leading cause of death in Europe.Together with cancer, these diseases
account for the vast majority of mortality and morbidity among adults
Europe and represent an enormous health problem with a major in Europe.The project will increase our knowledge of these common
socio-economic impact. We have assembled a large consortium, and deadly diseases and the mechanisms by which eicosanoids and NO
positioned at the forefront of eicosanoid and NO research. The trigger and maintain pathophysiological processes, with the long-term
goal of developing novel drugs and therapeutic strategies.
partners will carry out a multidisciplinary project, aiming to increase
the knowledge of these autacoids, and to develop novel therapeutic
strategies and medical treatments. We will carry out molecular
Aim
studies on key enzymes and receptors to elucidate biochemical The projects goal is to generate new knowledge about cardiovascular,
cerebral and neoplastic diseases.The work involves basic molecular
properties, catalytic mechanisms and structure-function
studies of proteins, investigations of gene regulatory mechanisms,
relationships. We will address the functional genomics of the cellular signalling mechanisms and functional genomics and proteomics
Eicosanoid and NO cascades to characterise gene expression approaches to identify new genes. In turn, this work will be translated
into applied and clinical research activities.Together with evaluations
profiles and regulation under normal and disease states, and identify
in animal models, clinical patient studies and programmes on drug
novel potential drug targets. New genes will be characterised using design,we expect to develop novel therapeutic strategies and medical
proteomics, structural genomics and model organisms. In parallel, treatments for several severe diseases. We will also create a long-
the partners will conduct cell biological work on gene regulation, lasting infrastructure for R&D activities, education, training,
exploitation and dissemination of results to users at multiple levels,
gene silencing, signalling systems and cross-talk between pathways. such as research organisations, funding agencies, patient associations,
This information will be used in studies of disease mechanisms such industry, and society in general.
as inflammation, immune responses and angiogenesis. In turn, these
insights in pathology will be translated into investigations of diseases Expected results
using animal models and clinical applications. The basic research It is envisaged that molecular work, including biochemistry, protein
together with applied and clinical studies will act in synergy to chemistry, studies of structure function relationships and enzyme
identify novel targets for pharmacological intervention and drug regulation will generate basic knowledge of the molecular
properties of the key proteins in the eicosanoid and NO cascades.
design for the treatment of patients suffering from cardiovascular, We will take advantage of the human genome sequence and employ
cerebral and neoplastic disorders. front-line technologies in functional genomics and proteomics

12
OVERARCHING
PROJECTS
research to identify genes that participate in the biological

responses elicited by eicosanoids and NO.Thus, we will carry out
a large integrated programme on systematic microarray analyses
Coordinator
for mRNA profiling of regulated genes in a variety of in vitro and in Prof. Haeggstrm, Jesper Z.
vivo model systems for disease processes. Using a proteomics
Division of Chemistry 2
approach, new genes will be characterised at molecular and
functional level, using an array of biochemical and biophysical Department of Medical Biochemistry and Biophysics
methods, structural genomics and model organisms. These joint
Karolinska Institutet
activities are expected to generate important insights to the
regulated expression of genes in the eicosanoid and NO cascades, Stockholm, Sweden
cross-talk between the pathways, and identification of novel genes
Phone: +46 8 524 87612
involved in the regulation and action of these autocoids, i.e. novel
potential drug targets. Fax: +46 8 736 0439
Along with this work, we will conduct work on cellular regulation Email: jesper.haeggstrom@mbb.ki.se
of eicosanoid and NO biosynthesis and action, including
Project web-site: http://www.eicosanox.org
complementary tasks on gene regulation, gene silencing expression
and function of receptors, intracellular signalling mechanisms and Key words: eicosanoids, nitric oxide, cardiovascular
cross-talk between pathways. This knowledge will in turn be disease, brain disease, neoplasia,
translated into studies of basic pathophysiological mechanisms, in inflammation, angiogenesis, drug
particular inflammatory and immune reactions, as well as development, therapy, molecular biology, cell
angiogenesis. Insight into the role of eicosanoids and NO in basic biology, genomics, proteomics
pathology will be connected to direct investigations of
cardiovascular, cerebral and neoplastic diseases, using animal models
and clinical applications on human tissues and patient studies.Thus, Partners
the basic research and applied and clinical studies will act in synergy Karolinska Institutet, Sweden
and facilitate efforts to identify novel targets for pharmacological
intervention and drug design. These joint efforts will allow University of Frankfurt, Germany
development of novel therapeutic strategies and medical Universit degli Studi di Milano, Italy
treatments for patients suffering from diseases of the cardiovascular
and central nervous systems and cancer. Fondazione Universit Gabriele Dnnunzio, Italy
Wolfson Institute for Biomedical Research, United
Potential applications Kingdom
Queen Mary & Westfield College, University of London,
Our project will increase our knowledge about these common and
United Kingdom
deadly diseases and the mechanisms by which eicosanoids and NO
trigger and maintain pathophysiological processes. In addition, we National University of Ireland, Ireland
intend to identify new drug targets, evaluate the therapeutic potential
Nicox Research Institute Srl, Italy
of recently developed lead structures, improve existing therapies and
develop novel drugs and therapeutic strategies. Universidad Autonoma de Madrid, Spain
Biolipox AB, Sweden
Queens University, Canada
University Clinics Charit, Humboldt University, Germany
Acronym: Eicosanox
Project number: LSHM-CT-2004-005033
EC contribution: 10 700 000
Instrument: Integrated Project
Duration: 60 months
Starting date: 01/01/2005

13
OVERARCHING ECRIN-RKP
PROJECTS
European Clinical Research Infrastructures Network

(ECRIN) - Reciprocal Knowledge Programme (RKP)
Summary
Based on the interconnection of national networks of clinical research
centres (CRCs) and clinical trial units (CTUs) the European Clinical
Research Infrastructures Network (ECRIN) programme is designed
to develop an infrastructure allowing for bottom-up harmonisation
of support, training, and practice of clinical research. ECRIN aims at
providing public or private (mainly biotechnology SME) sponsors with
a support for translational research and multicentre clinical studies
in Europe.The ECRIN consortium is based on national networks of
CRC / CTUs together with the European Forum for Good Clinical
Practice (EFGCP).A major objective of ECRIN consists of stimulating
Potential outcome
and facilitating the creation of centres and national networks,especially The ECRIN-Infrastructure project will be developed later and will
consist of the build-up of an infrastructure facilitating transnational
in the new member states, for their subsequent connection to the
clinical studies and including networking activities allowing for harmo-
European network. Connecting these national networks within a nisation of training, tools and practice.
broad European network will contribute to the critical mass at the Networking activities are designed to promote a harmonised
European level needed for the implement of European standards and implementation of good clinical practice, according to Directive
training regarding clinical research. The European Consortium of 2001/20/EC and Member State legislation, a harmonised training and
practice in clinical research, and communication with investigators,
clinical research infrastructures currently includes eight networks of
patients and citizens. Workgroups will cover the impact of national
CRCs and CTUs, covering six European countries representing 260 legislation on clinical studies, ethical issues, good clinical practice and
million citizens (Denmark, France, Germany, Italy, Spain, and Sweden), harmonisation of SOPs, data management and quality control
procedures.Topic-specific subnetworks,collection of biological material,
and comprising 112 different medical centres and hospitals conducting
and transnational cohorts will be promoted, while circulation of
1500 clinical studies. information will target the main actors of clinical research, i.e.,
investigators and researchers, scientific associations, the Cochrane
Objectives Collaboration, funding agencies, and industry partners, as well as
patients and patients associations. European Correspondents in each
The ECRIN-RKP project is designed to exchange information national network will participate in such networking activities.
regarding the organisation of national networks and their
Transnational access activity will facilitate the realisation of
environment. This ECRIN-RKP project is the first step of a wider
multinational studies through a panel of flexible services proposed to
ECRIN programme designed to build up an infrastructure promoting
the sponsors (however ECRIN will not act as a sponsor by itself).
a harmonised implementation of the EU Directives regarding clinical
Services provided will rather include consulting for centre selection,
research, and providing academic or biotechnology sponsors with a
funding opportunities, protocol review, ethical review, biostatistics,
support for the conduct of multinational clinical studies/trials in
data and safety monitoring committees, and insurance, whereas
Europe (the ECRIN Infrastructure project). Optimising the ECRIN
support will be provided for regulatory affairs,drug dispensation,data
Infrastructure project requires an in-depth reciprocal knowledge of
monitoring, pharmacovigilance and management of SAE, and data
all partners and of their national environment, leading to refinement
custody and intellectual property. Transnational access to ECRIN
of the content of items specific for infrastructure projects, namely
facilities will be delivered, after scientific, methodological and ethical
the networking activities, the transnational access activities and the
review, through a Co-ordination Team whose role consists of solving
joint research projects. Prepared by national workshops, the ECRIN-
problems raised by transnational studies with the help of European
RKP action is therefore based on a diagnostic step devoted to a
Correspondents in each national network.
comparative analysis (a workshop in Brussels on 16-17 December
2004, with three representatives per network), followed by a closure Joint research projects aim at improving the quality of the services
meeting (on 14-15 February 2004,in Brussels,with one representative delivered by the ECRIN-Infrastructure. This is achieved through a
per centre) designed to discuss which points require harmonisation European joint research programme in ethics, informed consent, and
and which services could be proposed for transnational access. gender issues.

14
OVERARCHING
PROJECTS
The project is designed on a progressive growth model of the initial national multicentre studies alongside the interconnection of skills and
network through the addition of new national networks (with special logistics. However, some EU countries still lack such networks.
attention provided to the new Member States),thereby increasing the
3 - ECRIN network
efficiency of the infrastructure.
The ECRIN consortium of clinical research infrastructures includes
In addition, this SSA allowed to participate in the preparation of the
eight networks of clinical research centres (CRCs) and clinical trial units
FP7 Technology Platform 'Innovative Medicines for Europe' (Barcelona
(CTUs), covering all the medical fields. Currently, these networks cover
workshop). ECRIN also participated in the debate on transparency
six countries representing 260 million citizens.Therefore they reach the
in clinical trials, and will co-ordinate a communication event on clinical
critical mass both at their country level and at the EU level.No equivalent
research, targeting EU citizens and patients associations.
infrastructure exists in Europe.
In addition, the Canadian participant (FRSQ-GEREQ) extends the
Participants capacity of ECRIN to perform clinical studies on the North American
The ECRIN consortium is designed to provide a European not-for- continent, using data management tools compatible with FDA
profit platform for the investment and realisation of trans-European requirements.
clinical research projects. ECRIN is not directed towards a specific Closely associated with scientific associations and investigators, acting
speciality or disease category, but will foster transfer of best research through disease-specific networks of practitioners, these centres have
practice from speciality to speciality all over Europe. the capacity to enrol patients in a wide range of clinical studies,
1 - CRCs and CTUs particularly in rare diseases, orphan drugs, paediatrics, biotherapy.
The development of Clinical Research Centres (CRCs) in Europe

occurred in the 1990s in some countries with the support of health or
research ministries, of universities, hospitals, and government agencies,
Coordinator
and of foundations.Allowing investigation through a team of study nurses, Demotes-Mainard, Jacques
physicians, specific beds and equipment, each centre acts as a facility CIC INSERM-CHU de Bordeaux
providing support for research projects, acting through strong CHU Haut-Lvque,Avenue de Magellan
connections with physicians from various medical fields involved in the 33604 PESSAC, France
design of the project, in its realisation, and in the enrolment of patients. Phone: +33 55765 6170
Clinical research centres also provide expertise for drug registration, Fax: +33 55765 6168
and represent a bench-to-bedside link between research laboratories
Email: demotes@bordeaux.inserm.fr
and clinical studies,either through clinical applications of new strategies,
Project web-site: www.ecrin.org
or through the investigation of patients for genotype/phenotype, or
pathophysiological studies. Key words: clinical research, infrastructures, harmonisa-
tion, transnational studies
The concept of Clinical Trial Units (CTUs) developed earlier and has
extended in Europe over the past ten years. Not necessarily based in a
hospital, their main activities consist in providing specialist knowledge Partners
for planning, conducting, and reporting clinical trials (including phase I, Clinical Research Centres / Clinical Trial Units Network,
phase II, and phase III trials) that may include from several patients to Denmark
several thousands of patients. Their task includes design of the trials, Rseau Franais des Centres dInvestigation Clinique
implementation of the randomisation of the patients, case record form INSERM-Hpitaux, France
(CRF) development and collection, database building and checking, Rseau Franais dunits dessais cliniques, France
analysis of the data, and reporting of the results. Their staff includes
Netzwerk der Koordinierungszentren fr Klinische Studien,
statisticians, project managers, data managers, and computer engineers.
Germany
They are closely collaborating with clinicians, supporting them in all the
Consorzio Italiano per la Ricerca in Medicina, Italy
steps of clinical trials. Most of the CTU are also performing other types
of clinical studies (diagnostic evaluation for instance) and epidemiological Istituto Mario Negri. Italy
studies. Medical teams participating in the trial may be helped for data Spanish Clinical Research Network, Spain
collection by study nurses or research assistants, or by CRCs. This Clinical Research Centres / Clinical Trial Units Network,
illustrates the complementarity between both structures, CTUs often Sweden
provide CRCs with methodological and data management support.Many European Forum for Good Clinical Practice
CRCs are mainly involved in the early phases of drug and device
development, CTUs in later ones.
2 National networks of CRCs/CTUs Acronym: ECRIN-RKP
In most countries,the organisation of the first national networks only EC contribution: 225 000
appeared recently, permitting critical mass achievement, and leading to Instrument: Specific Support Action
Duration: 12 months
the standardisation of practice in these countries, and the facilitation of Starting date: 13/05/2004

15
Cardiovascular
Bloodomics 18
EVGN 20
MOLSTROKE 24
EuroClot 26
Myocardial Repair 28
CARDIOVASCULAR Bloodomics
Identification of risk genes for atherothrombosis in

coronary artery disease by transcriptome and proteome
analysis and high throughput exon resequencing
Summary The clinical challenge
Coronary artery disease and atherothrombosis cause more deaths The risk of cardiovascular disease is determined by the interplay
in Europe than any other disease.About 600 000 people are diagnosed between an individuals genetic background,lifestyle and environment.
Twin studies have clearly demonstrated a genetic component for
with myocardial infarction (MI) yearly, with 50% of cases being fatal
cardiovascular disease and several risk genes have already been
and many of the survivors experiencing a reduction in quality of life. discovered. However, genetic markers to predict the risk of
Early identification of individuals at risk has proven difficult in the past. atherothrombosis are currently not available. The absence of such
With state-of-the-art tools and technologies at hand,the Bloodomics markers means that there is a risk of an excess of preventative
project aims at discovering markers associated with a higher risk for treatment. As an example, long-term aspirin use can cause bleeding
and its benefits for the population at large become marginal if it is
arterial thrombus formation and MI.
used too widely.
In the post-genome era, the Bloodomics project makes use of the
completed human genome sequence as well as employing high Aim
throughput platforms for sequencing, genotyping for single nucleotide
The Bloodomics project aims to discover genetic markers for the
polymorphisms (SNPs), gene expression analysis, proteomics and
prediction of thrombus formation in coronary artery disease and to
RNA interference. Integrating the knowledge generated with these design better anti-thrombotics for improved prevention and
different platforms with clinical information from MI patients will lead treatment.
to the identification of genetic markers for atherothrombosis.
The Bloodomics project focuses on the genetics and cell biology of Expected results
platelets,since we hypothesise that the response of platelets is critical During the course of the project, 300 candidate platelet genes that
in determining whether thrombus formation will lead to arterial blood are potentially associated with arterial thrombus formation will be
vessel occlusion. Initially, we will identify platelet genes and gene identified using complementary approaches.Three different routes will
variants that contribute to atherothrombosis. Later we will determine be used to discover candidate genes. First, we will define the platelet
the physiological role of the corresponding proteins and characterise response to several well-characterised agonists in a large group of
healthy individuals and then identify differences in mRNA and protein
the signalling pathways involved. This comprehensive approach will
abundance using microarray and proteomics in extreme end samples.
provide new insights into the causes of coronary artery disease and Second, we will compare the transcriptome of platelets from MI
atherothrombosis, eventually leading to the development of new patients and controls. Finally, we will discover novel genes important
strategies for prevention and novel anti-platelet drugs for treatment. for platelet function by studying rare pedigrees with unexplained
autosomal recessive bleeding disorders of the platelet type.
The Bloodomics consortium has brought together a multi-disciplinary
Based on the common disease-common alleles hypothesis,the genetic
team from 14 world leading academic centres across Europe. Five
variants in the 300 candidate genes will be identified by exon
leading clinical coronary artery disease units,groups specialized in cell resequencing in a reference panel of 48 individuals.This will lead to
biology and signalling, haematopoiesis and proteomics will work the discovery of common alleles.To determine whether certain alleles
together with Europe's premier genome centre in this challenging do confer a statistically significant risk to coronary artery disease or
discovery programme.The programme will be underpinned by a team related events, we will analyse the frequency of these polymorphisms
in a Phase-I case-control study using the DNA of 2 000 well-
of ten bioinformaticians and four statisticians. In addition, two young
characterised patients and 2 000 common controls. By this direct
companies,Domantis Ltd,an antibody engineering company and Trium approach alleles that may confer a relative risk of at least 1.5 will be
Analysis Online, a company developing online solutions for discovered.These putative risk genes (predicted to be 5-10% of the
biostatistics, epidemiology and informatics, will make critical initial 300 candidate genes) will require further investigation in a Phase-
contributions. By adding 30 new positions to the existing 160 staff in II case-control study with another 3 000 patients and controls. We
will be able to achieve this because the Bloodomics DNA repository
the affiliated institutes, Europes commitment to basic and
provides access to samples and clinical phenotype information from
translational research in coronary artery disease and over 10 000 patients with coronary artery disease and 10 000
atherothrombosis will be strengthened. common controls.

18
CARDIOVASCULAR
Structure of the VWF-binding Coordinator

domain of GpIba: Ribbon
representation of GpIba.The Dr.Willem H. Ouwehand
NH2-terminal hairpin, called European Cardiovascular Genetics Foundation (ECGF),
finger, is coloured blue; the Department of Hematology,
eight leucine-rich repeats are University of Cambridge,
green.The COOH-terminal Long Road
flanking region is coloured red
and contains a disordered Cambridge CB22PT, United Kingdom
loop (residues 227-241) Phone: +44-1223-548 037
called switch. Disulfide
Fax: +44-1223-548 136
bridges are indicated in yellow
ball-and-stick representation. E-mail: willem.ouwehand@nbs.nhs.uk
Project website: www.bloodomics.org
Key words: coronary artery disease, atherothrombosis,
We will integrate the results obtained in functional and cell signalling
myocardial infarction, platelet, RNAi,
studies with the transcriptome, proteome and genetic data of a large
microarray, proteomics, genotyping,
number of healthy individuals and patients. It is expected that this will
sequencing, case-control study, clinical cohort
result in a library of platelet functional signatures and genetic
fingerprints. This integrated library will be a powerful tool towards
personalised medicine in coronary artery disease. Partners
Finally, the application of RNA interference in human haematopoietic The Chancellor, Master and Scholars of the University of
stem cells will further allow us to gain insight into the function of Cambridge, United Kingdom
novel platelet proteins that are discovered within the candidate gene
programme. In combination with an antibody production pipeline, it European Cardiovascular Genetics Foundation, Cambridge,
is expected that we may identify novel targets for drug development. United Kingdom
Genome Research Ltd/Wellcome Trust Sanger Institute,
Potential applications Hinxton, United Kingdom
Universitair Medisch Centrum Utrecht,The Netherlands
Identification of individuals at risk is paramount for an effective
preventative health care strategy that aims at reducing the morbidity Academisch Ziekenhuis bij de Universiteit van Amsterdam,
and mortality of heart disease. Future improvement in coronary care The Netherlands
is also dependent on new and safe drugs.The Bloodomics project will
Katholieke Universiteit Leuven, Belgium
make contributions in both of these areas. First, genetic risk markers
for atherothrombosis will be discovered. Second, novel targets will Stichting Sanquin Bloedvoorziening, Amsterdam,
be identified and development of anti-thrombotic drugs will be The Netherlands
supported by structural studies. Finally, the project will generate
LURIC Datenbank Gesellschaft brgerlichen Rechts,
population genetics data from large cohorts of patients and controls
Freiburg, Germany
from different European member states.
Associazione per lo studio della trombosi in cardiologia,
Pavia, Italy
Trium Analysis Online GmbH, Munich, Germany
Medical Research Council/Biostatistics Unit, Cambridge,
United Kingdom
Acronym: Bloodomics Domantis Ltd, Cambridge, United Kingdom
Project number: LSHM-CT-2004-503485 University of Leicester, United Kingdom
University College Dublin, Ireland
Subcontracting: National Institute for Biological Standards
Duration: 48 months
and Control, Potters Bar, United Kingdom
Major Diseases Research (2003-2005) 19

CARDIOVASCULAR EVGN
European Vascular Genomics Network

Summary molecular understanding of cardiovascular disease, for identifying new
diagnostic measurements and developing new pharmacological, gene
Cardiovascular disease (CVD) caused 51% of deaths in Europe in 2001. and cell-based therapies. The European Vascular Genomics Network
Coronary heart disease and stroke, which result from atherosclerosis, (EVGN) assembles the necessary critical mass and promotes
constitute 80% of CVD. Better prevention and treatments have halved multidisciplinary interactions by uniting 25 world-leading basic and
age-specific incidence, but the ageing population and adverse trends in clinical institutions from nine European countries.It focuses on the three
obesity and diabetes threaten these improvements. There is also an areas with greatest therapeutic potential:
alarming increase in heart failure, the end stage of coronary heart
1) endothelial dysfunction, an early critical event in atherosclerosis and
disease.Future advances depend on developing entirely new strategies.
hence a target for prevention;
Genomics and proteomics together open up fresh horizons for
2) plaque instability,responsible for precipitating thrombosis and hence
most life-threatening acute events; and
3) therapeutic angiogenesis,either conventional or cell-based to recover

ischemic organ function and reduce heart failure. Our research
armoury spans genomics,proteomics,molecular biology,cell biology,
gene transfer and genetic modification in mice, and integrative
pathophysiology in man.The EVGN will maximise the scientific and
commercial potential of European vascular biology by electronic
data-sharing and communication networks, shared research tools,
and exchange and training programmes. The EVGN will train
tomorrows lead investigators through a European training
programme for PhD students,which will also address adverse gender
balance and encourage excellence in eastern Europe, which suffers
high prevalence of CVD.
Expression of the adhesion molecule VCAM-I (in brown) by the endotheli-

um of a mouse fed an atherogenic diet for 10 days. Lumen on the right

20
CARDIOVASCULAR
Atherosclerotic plaques (in red) at the surface of

the aorta from a mouse deficient in apolipoprotein E
Problem Aim
Cardiovascular disease is the leading cause of death in the European 1.The EVGN networks and structures the leading European groups
Union, accounting for over 1.5 million deaths each year (5 million already involved in an uncoordinated way in applying genomics to
in Europe). Nearly half (42%) of all deaths in the EU (51% in Europe) vascular biology research, so as to maximize their potential. The
in 2001 were from cardiovascular disease, while cancer caused 20%. network focuses on the 3 research areas, endothelial dysfunction,
Ischemic heart disease and stroke, which have a predominant unstable atherosclerosis and therapeutic angiogenesis that appear most
vascular origin resulting from atherosclerosis, account for most likely to generate benefits for patients.
deaths from cardiovascular disease (80%). Age-specific incidence
a) Endothelial dysfunction is an early prognostic marker and
rates for cardiovascular disease have fallen by half over the past 30
important pathological mechanism underlying the development
years in the economically advanced European nations, as the result
of atherosclerosis.A major goal of the EVGN is to develop new
of better prevention and treatments based on growing knowledge
diagnostic tools and means to correct endothelial dysfunction,
of vascular biology. Although these measures are becoming widely
which could have a major impact on atherosclerosis prevention.
disseminated, an additional dramatic effect on cardiovascular
disease incidence and mortality is unlikely to be achieved without b) Potentially fatal myocardial infarctions and strokes are
the development of entirely new therapeutic and preventive precipitated by acute atherosclerotic plaque instability, either
strategies. Recent advances in genomics open new avenues to surface erosion or rupture of the fibrous cap.The EVGN is aimed
understand the molecular basis for cardiovascular disease and at identifying the genes that mediate plaque instability in humans,
hence design new diagnostic tests and classes of drugs based on designing diagnostic tests to identify high-risk individuals and
hitherto unknown target genes.Therapeutic approaches including developing drugs to decrease risk of rupture.
DNA vaccination, gene therapy and cell therapy may revolutionise
the prevention and treatment of atherosclerosis. Accordingly, the
European Vascular Genomics Network (EVGN) is a timely initiative
aimed at maximising the impact of the post-genome era on vascular
biology so as to optimise the conversion of research results into
concrete health, social and economic benefits.

CARDIOVASCULAR
c) Insufficient neoangiogenesis is an integral

component of loss of organ function
following chronic ischaemia or acute
ischaemic injury due to atherosclerotic
plaque rupture and myocardial infarction.
Therapeutic angiogenesis promoting the
growth of new vessels from existing vessel Expression of the Tissue Factor,
wall cells, in conjunction with the the main initiator of thrombus
recruitment of circulating endothelial formation in myocardial
progenitor cells (EPCs),is therefore viewed
infarction (in red), in a human
as a highly promising strategy to
atherosclerotic plaque that
revascularise ischaemic tissues and thereby
contains debris from apoptotic
improve functional recovery of injured
cells (in brown)
organs. A major goal of the EVGN is to
identify genes involved in differentiation,
homing and expansion of EPCs.
2.The EVGN acts as an interface between basic
scientists and clinician scientists to promote
and accelerate the transition of knowledge in
vascular biology to improve diagnosis and
treatment of atherothrombotic diseases.
Potential applications
3.The EVGN provides enriched and continued education in vascular
biology. The EVGN proposes to train tomorrows leading The chosen study areas 1) endothelial dysfunction, 2) atherosclerotic
investigators by creating a European training programme in vascular plaque instability and 3) therapeutic angiogenesis represent three
biology for PhD students based in part on a summer school. phases of the cardiovascular disease continuum. Endothelial
dysfunction underlies atherosclerosis progression and is a fertile area
4.The EVGN jointly manages,disseminates and promotes exploitation for early diagnosis and prevention.Atherosclerotic plaque instability
of the knowledge generated and accumulated within the network. precipitates most life-threatening manifestations of atherosclerosis
and as such is a key unexplored area for novel therapies, not based
on risk factor modification but on targeting the pathology.Therapeutic
Expected results angiogenesis is a leading edge new technology that promises to
1.To define the molecular mechanisms underlying endothelial and ameliorate end organ damage following acute cardiovascular events.
smooth cell dysfunction and discover new preventive strategies in In particular it may tackle the alarmingly escalating incidence of heart
atherosclerosis. failure. Each of the three priority areas is ripe for the genomic
approach, since each depends on understanding complex regulatory
2.To develop and standardise new animal models of plaque rupture, pathways in molecular detail. Each has potential for the development
to improve non-invasive in vivo detection of unstable plaques, and of new diagnostic and therapeutic strategies that will provide
to identify molecular targets whose selective activation/inhibition permanent benefits for patients.
will tend to limit plaque progression or promote atherosclerotic
plaque stability.
3.To identify novel genes, gene products, or signalling pathways that
are involved in, and could be targets for, selective modulation of
angiogenesis/vasculogenesis
4.To define the most suitable preventive and/or therapeutic strategies
for use in clinical care of ischaemic vascular diseases.

22
CARDIOVASCULAR
Centre for Biopharmaceutical Sciences, University of

Coordinator Leiden,The Netherlands
Dr Tedgui,Alain Department of Biochemistry,Academic Medical Center,
Inserm U541 University of Amsterdam,The Netherlands
Hpital Lariboisire Universita Vita-Salute San Raffaele, Italy
41 blvd de la Chapelle Institut fuer Pathophysiologie, Medizinische, Universitaet
Innsbruck, Austria
75475 Paris - Cedex 10, France
A.I.Virtanen Institute, University of Kuopio, Finland
Tel: +33 1 44 63 18 66
Institute for Cancer Research and Treatment, University
Fax: +33 1 42 81 31 28 of Torino, Italy
Email:Alain.Tedgui@larib.inserm.fr Experimental Medicine and Gene Therapy Section,
Project web-site: http://www.evgn.org/ National Institute of Biostructures and Biosystems, Italy
Key words: cardiovascular disease, vascular biology, ather- St George's Hospital Medical School, University of
osclerosis, endothelium, angiogenesis, inflam- London, United Kingdom
mation Department of Molecular Biology, Institute of
Partners Microbiology,The Hebrew University of Jerusalem, Israel
Department of Reproductive and Vascular Biology,
Bristol Heart Institute,The University of Bristol,
University of Birmingham, United Kingdom
United Kingdom
University College London, United Kingdom
Klinikum der J.W.Goethe-Universitt, Germany
Division de Cardiologie, Fondation pour Recherches
Chancellor, Masters and Scholars of the University of
Mdicales, University Hospital of Geneva, Switzerland
Cambridge, Addenbrookes Centre for Clinical
Investigation, United Kingdom Centre Europen de Recherche en Biologie et en
Mdecine, IGBMC, Illkirch, France
Department of Pharmacology, Cardiovascular Research
Institute Maastricht (CARIM),The Netherlands Ark Therapeutics Group Limited, London, United
Kingdom
Center for Molecular Medicine, Karolinska Institutet,
Sweden Technoclone GmbH,Vienna,Austria
Fondazione IFOM Istituto FIRC di Oncologia moleculare, Inserm-Transfert SA, Pons, France
Italy
University Hospital, Zrich, Switzerland Acronym: EVGN
Department of Vascular Biology and Thrombosis research, Project number: LSHM-CT-2003-503254
Medical University of Vienna, Austria Instrument: Network of Excellence
Medizinische Klinik und Poliklinik, Johannes Gutenberg- Duration: 60 months
Universitt Mainz, Germany
Klinik und Poliklinik Innere Medizin III, Universitt des
Saarlandes, Germany
Institute for Cardiovascular Research (ICaR-VU),
VU Medical Centre,The Netherlands

CARDIOVASCULAR MOLSTROKE
Molecular basis of vascular events leading

to thrombotic stroke
Summary to identify new markers to more appropriately predict the possible
development of stroke and to identify those subjects with potential
Stroke kills about 5 million people annually and is also the leading benefit from preventive therapy.
cause of disability and dementia in adults. Early recognition of Ischemic strokes account for 83% of all strokes and thrombotic strokes
individuals at risk for stroke would significantly alleviate the heavy represent 52% of all ischemic strokes. Thrombotic stroke is a
consequence of atherosclerotic disease and is caused by destabilisation
social and economical burdens due to stroke. Advances in of atheromatous plaque with ensuing thrombosis and vessel occlusion
identification of vulnerable individuals require development of locally or distally due to embolism.A large body of data supports that
entirely new strategies. Stroke is triggered by thrombosis occurring inflammation plays a major role in the pathophysiology of atherosclerosis
and stroke.Understanding the mechanisms responsible for the initiation,
after rupture of atherosclerotic plaques, and MOLSTROKE focuses
establishment, maturation and persistence of atherosclerotic lesions is
on identifying pathogenetic molecular mechanisms and vascular far from being fully accomplished. The current research focus is the
protagonists defining vulnerable plaques and contributing to plaque definition of new criteria to recognise vulnerable plaques and vulnerable
patients. These criteria should be based on better definition of the
rupture. MOLSTROKE assembles seven partners with
pathogenetic mechanisms of plaque rupture. They should utilise
multidisciplinary backgrounds and exploits innovative technological inexpensive and relatively non-invasive screening methods that are
approaches together with testing of novel pathogenetic hypotheses. capable of adding predictive value to measurements of established risk
factors. Moreover, they should be readily applicable to an asymptomatic
The priority research areas of MOLSTROKE consist of 1) population.
concomitant wide genomic and histoproteomic screening of lesional
vascular tissue to identify novel pathogenetic markers, 2) early Aim
inflammatory events, which are the key to atherosclerosis
The main scientific and technological goals of MOLSTROKE are to
progression and hence primary prevention, and 3) atherosclerotic identify mechanisms and molecular protagonists that participate in
plaque instability, which leads to the acute clinical thrombotic events. the vascular pathological events leading to thrombotic stroke.
MOLSTROKE addresses objectives using two concomitant
The proposed investigations will implement novel technologies of
strategies.
differential display of unknown genes and vascular tissue arrays.Thus,
The first strategy is non-hypothesis driven and will use wide-screening
weighted identification of stroke denominators can be accomplished technologies together with novel bioinformatics tools to identify genes
and thereby lead to improved diagnostic and treatment modalities. and proteins preferentially expressed in atheromatous plaques as well
The research armoury spans genomics, tissue arrays, molecular as molecular, biochemical, and cellular patterns potentially involved in
plaque rupture.
biology, cell biology, immunology, biochemistry, gene transfer, animal
models and integrative bioinformatic software tools. The second strategy is based on hypothesis-driven studies,taking into
consideration current knowledge of the pathogenesis of vascular
MOLSTROKE will maximise the scientific, educational and lesions at the level of molecular protagonists and mediators of
inflammation and vascular cell responses to inflammation.
commercial potential of the proposal by electronic data-sharing,
communication networks, shared research tools, and training
programmes. Expected results
identification of genes of potential pathogenetic importance
Problem generation and use of novel bioinformatics tools
Stroke is a major killer since about 5 million people die each year of localise and quantify differentially expressed proteins in symptomatic
this disease. Stroke is also the major cause of disability in adults, and atherosclerosis
the second most important cause of dementia in western countries.
identify molecular targets of novel therapeutic approaches to
Among those who survive a stroke,the risk of a second stroke is very
prevent symptomatic atherosclerosis and stroke
high. Currently known risk factors for stroke (age, cardiovascular
diseases, atrial fibrillation, arterial hypertension, diabetes mellitus, strategy for immunotherapy of atherosclerosis and stroke
carotid stenosis) are of low sensitivity and specificity. It is important prevention

24
CARDIOVASCULAR
Coordinator
Prof. De Libero, Gennaro
Experimental Immunology
Department of Research
University Hospital Basel
4030 Basel, Switzerland
Phone: +41 61 2652365
Fax: +41 61 2652350
Email: gennaro.delibero@unibas.ch
Prof. Resink,Therese
Signal Transduction
Department of Research
University Hospital Basel
4030 Basel, Switzerland
Email:Therese-J.Resink@unibas.ch
Project web-site: to be constructed
Key words: stroke, atherosclerosis, inflammation, angio-
genesis, lipids, plaque instability
Partners
Dr Biedermann, Barbara
Department of Internal Medicine
University Hospital Bruderholz
Work flow in the MOLSTROKE project
Binningen, Switzerland
Prof. Hansson, Goran. K.
Department of Medicine
strategy for lipid-based immunomodulation of atherosclerosis Karolinska Hospital and Center for Molecular Medicine
Karolinska Institute
development of new therapeutic strategies (anti-inflammatory
Stockholm, Sweden
and/or anti-angiogenic) for prevention of thrombotic stroke
Dr Bochkov,Valery
translational impact to other diseases in which inflammation and Department of Vascular Biology and Thrombosis
excessive angiogenesis occur (e.g. cancer, diabetic retinopathy, Research
arthritis, psoriasis)
University of Vienna
Vienna, Austria
Potential applications Prof. Ricciardi Castagnoli, Paola
Prevention and therapy of stroke. Universit Milano Bicocca
Milan, Italy
Prof.Wick, Georg
Institute for Biomedical Ageing Research
Austrian Academy of Sciences
Innsbruck, Austria
Acronym: MOLSTROKE
Instrument: Specific Targeted Research Project
Duration: 36 months

CARDIOVASCULAR EuroClot
Genetic regulation of the end-stage clotting process

that leads to thrombotic stroke
Aim
We aim specifically to identify the major genes involved
in variations of the end-stage clotting process and
investigate the role of these novel genes (and existing
candidate genes) in the pathogenesis of stroke across
Europe. EuroClot will study stroke intermediate
phenotypes in over 3000 twins from the
GenomEUtwin project involving eight countries and
700 subjects from extended families. Genes will be
validated in 1000 stroke cases including those from the
large European prospective MORGAM study. Cross-
European differences in allelic frequencies will be
examined along with their relative impacts.Phenotyping
will be standardised and harmonised and a European
database established. Close links with European SMEs
will ensure that all findings from EuroClot are
maximally exploited to develop future novel diagnostics
and therapeutic targets.
Expected results
Identification of susceptibility loci and genes for the
end stages and final common pathways of clotting.
Assessment of the importance of these genetic
factors in the general European population.
Summary
Discovery of how identified genetic variants vary in influence and
Thrombotic stroke is a disabling condition affecting an estimated 650,000 frequency of stroke in Northern and Southern Europe.
Europeans annually, with considerable mortality and costing over 30 Identification of genes controlling fibrin formation or activation that
billion/yr. This project aims to unravel the genetic basis of thrombotic will become important diagnostic tests used in conjunction with
stroke leading to new diagnostics and drug targets. other markers or genes.
Better understanding of the mechanisms involved providing potential
new drug targets for the prevention or treatment of early stroke.
Problem
Collaboration with SMEs to exploit findings for clinical benefit.
Genetic factors account for a substantial component of the incidence
and mortality of stroke.There is little effective therapy. EuroClot aims Generation of genotypic and phenotypic data for concordant and
to identify and validate potentially therapeutically useful genes discordant twin pairs for future studies evaluating environmental
associated with thrombotic stroke using a novel approach. Stroke is effects on stroke pathogenesis and expression.
a complex end-point disease involving the interaction of many Stimulation of interest in thrombotic stroke research.
pathologic processes, such as vessel wall atheroma, hypertension,
platelet function & coagulation. EuroClot focuses on uncovering the Development of the clinical, genetic, and experimental EuroClot
genes that control the end-stage of the coagulation process that leads database.
directly to the production of the thrombus (clot) that causes vascular Position European researchers as leaders in clotting and stroke
obstruction and tissue death. Clinical studies indicate that alterations research.
in fibrin structure and/or function create a prothrombotic phenotype,
which increases vascular risk.Twin studies have shown a substantial
genetic component to levels of activation peptides and the final
common pathway of thrombus (fibrin structure/function).

26
CARDIOVASCULAR
Coordinator
Prof. Spector,Tim
Twin Research Unit
St Thomas Hospital
Lambeth Palace Road
London SE1 7EH, United Kingdom
Phone: + 44 20 7188 6765
Fax: + 44 20 7188 6718
E-mail: tim.spector@kcl.ac.uk
Project web-site: in development
Key words: cardiovascular system, stroke, genetic, clotting
factors
Partners
Prof. Grant, Peter
Academic Unit of Molecular Vascular Medicine
Leeds Institute of Genetics, Health and Therapeutics
Leeds General Infirmary
Leeds, United Kingdom
Prof. Rosendaal, Frits
Department of Clinical Epidemiology
Leiden University Medical Centre
Leiden,The Netherlands
Prof. Palotie,Aarno
Potential applications Finnish Genome Centre
Potential new drug targets for the prevention of or treatment of early University of Helsinki,
stroke by reducing the tendency to clot.
Helsinki, Finland
Development of novel therapeutic targets for the prevention of Prof. Evans,Alun
thrombotic stroke using translational approaches in collaboration
with appropriate SMEs in Europe. Department of Epidemiology and Public Health
Mulhouse Building
Development of potential novel diagnostic tests for stroke risk using
combinations of clotting factors and genetic tests in collaboration Belfast, United Kingdom
with SMEs in Europe. Dr Stazi,Antionia
Centro Nazionale di Epidemiologia
Sorveglianza e Promozione della Salute (CNESPS)
Rome, Italy
Prof. Pedersen, Nancy
Department of Medical Epidemiology and Biostatistics
Stockholm, Sweden
Acronym: EuroClot Prof. Soria, Jose Manuel
EC contribution: 1 500 000 Thrombosis and Haemostatis Unit
Duration: 36 months Hospital de la Santa Creu i Sant Pau
Starting date: 01/01/2005 Barcelona, Spain

CARDIOVASCULAR Myocardial Repair
Clinical experience with bone marrow cells and

myoblasts transplantation for myocardial repair
Summary resources from each participating centre. The intention of this SSA
project is to enable the consortium to make appropriate exchanges
Heart failure caused by ischaemic heart disease is one of the most of information, reciprocal training visits as well as co-operative
common causes of morbidity and mortality across Europe. It is analyses of pooled data. Summary of existing pooled data will be
especially high among elderly people, but post-infarction myocardial submitted for publication by participating team leaders. In addition,
injury is also a major cause of disability in younger survivors from two international conferences on stem cell therapies and three
myocardial infarction.The project is dedicated to stimulate state-of- workshops for practitioners will be organised.
the-art research on the clinical applications of autologous stem cells,
including bone marrow-derived stem cells as well as myoblasts, to the Problem
regeneration of heart muscle in irreversibly damaged post-infarction
Heart failure due to myocardial infarction is a result of myocardial
regions.The consortium includes most experienced European clinical tissue loss. Preclinical research and initial clinical experience suggests
researchers in the field, which already had accomplished the phase I a possibility of myocardial regeneration by cell transplantation.
clinical trials in participating centres.
The researchers from participating centres have agreed to coordinate Aim

their future clinical trials on stem cell transplantation for myocardial The purpose of the project is to enhance the exchange of information
regeneration in patients with post-infarction heart failure, as a result on clinical experience with cell transplantation between leading
research groups and to summarise the European experience with
of the proposed project. This will include analysis of pooled clinical myoblast and bone marrow-derived cells transplantation in patients
data obtained in participating centres, reciprocal exchange of with post-infarction heart failure.
information on cell culture and cell preparation for transplantation.
This will also include standardisation of clinical protocols aiming at Expected results
evaluation of the clinical efficacy of myocardial replacement therapy It is assumed, that as a result of the proposed project, the exchange
as well as hands-on training of different techniques of cell delivery, of information and co-operative reciprocal visits in participating
including percutaneous cell transplantations, in particular trans- centres would further advance clinical research aiming at the myoblast
transplantation in comparison to other totipotent cells as bone
coronary arteries bone marrow stem cell delivery protocols as well
marrow cells for myocardial regeneration.
as trans-ventricular and trans-cardiac-veins myoblast injection
techniques.As a result of further integration of the consortium, it is
expected to stimulate formation of a common future phase III studies
Establishing clinical protocols for the use of cell transplantation for
at international level, especially with an option of submitting future
the treatment of post-infarction heart failure.
Integrated Project application within the 6th Framework Programme.
The current project of a Specific Support Action project is focused

on coordination of individual studies and integration for future pan-
European research. Thus, the continuation of the current clinical
experiments within phase I and II studies will be performed with

28
CARDIOVASCULAR
Coordinator
Siminiak,Tomasz
University School of Medical Sciences, Poznan
Department of Cardiology
Ul. Juraszow 7/19
60-479 Poznan, Poland
Phone: +48 61 8212422
Fax: +48 61 8212 319
tomasz.siminiak@usoms.poznan.pl
Project web-site: under construction
Key words: cardiology, medicine, muscle system, stem
cells, organ regeneration, cell therapy
Partners
Hpital Europen Georges Pompidou, Paris, France
Instut de Ciencias del Corazon,Valladolid, Spain
University of Rostock, Germany
3rd Medical School, Charles University Prague, Czech
Republic
University Hospital, Clermont-Ferrand, France
Vilnius University, Lithuania
Polish Academy of Science, Poznan, Poland
University of Rotterdam,Thoraxcenter,The Netherlands
Acronym: Myocardial Repair

Project number: LSSM-CT-2004-511992
EC contribution: 400 000
Instrument: Specific Support Action
Duration: 30 months

Diabetes
Diabesity 32
EXGENESIS 34
EUGENE 2 36
TONECA 39
IMMIDIAB 41
DIABETES Diabesity
Novel molecular targets for obesity and type 2 diabetes
Summary Expected results

The Diabesity project brings together basic and clinical scientists with Using a combination of invertebrate and mammalian genetics,
Diabesity expects to firstly identify several genes involved in the
the joint aim of identifying new genes implicated in obesity and diabetes pathogenesis of diabesity.These potential drug targets will then be
(diabesity) and to develop strategies for validating these genes as targets characterised by molecular and physiological studies resulting in the
for future pharmacological manipulation.We will study how these genes localisation of the site of expression of the targets and an under
standing of their functional roles in diabesity. Once characterised,
interact with hypothalamic pathways that regulate appetite and
potential targets will (by molecular genetics and phenotypical
metabolism using multiple approaches to establish the functional role analyses) be identified as playing major roles in diabesity, thereby
of genes in regulating metabolism, body weight and composition. Using providing validated novel drug targets and pharmaceutical therapies
that appropriately address diabetes and obesity.
this approach we aim to identify several novel, validated drug targets
for the treatment and prevention of diabesity.
Problem New knowledge generated by Diabesity, primarily novel drug targets
and potential pharmaceutical therapies, will be translated into
The rapid increase in the prevalence of obesity, type-2 diabetes, and applications that directly enhance human health by bringing basic
associated complications is a major global health problem. In Europe knowledge through to clinical application. To this end, both
alone, approximately 33 million adults will be suffering from diabetes fundamental and applied research will be supported,with an emphasis
by 2010. Obesity, which is a major recognised risk factor for type-2 on integrated, multidisciplinary, and coordinated efforts that address
diabetes,is itself rapidly increasing in prevalence resulting in a diabesity the present fragmentation of European research and increase the
epidemic.The current cost of type-2 diabetes in the European Union competitiveness of the European biotechnology industry.By identifying
is 15 billion per year, and medical complications arising from diabetes potential new drug targets for the treatment and prevention of
account for up to 8% of total health costs in Europe. For most people, diabesity we will provide pharmacological and biotechnological SMEs
neither dieting nor current pharmacological interventions are effective with the possibility to develop novel pharmaceutical therapies.
in achieving long-term weight reduction. Dieting is largely ineffective
because once a chronically overweight state has been attained,the brain
interprets dieting as a threat to survival, and the hypothalamic control
systems of the brain reduce our metabolism and attempt to maintain Coordinator
body weight, i.e. our brains defend our existing energy stores.Thus to Prof. Dickson, Suzanne L.
prevent and treat diabesity, we must develop approaches to modulate
Prof. Dickson, Suzanne L.
the ways in which the brain controls metabolism, body weight and
composition. Department of Physiology, Medicinaregatan 9A
Gteborg University
Aim Box 434
Diabesity aims to combine neurophysiological, neuroanatomical, and 405 30 Gteborg, Sweden.

systems physiological approaches to establish the functional role of Phone: +46 31 773 3568
genes in regulating body composition, in order to understand how E-mail: suzanne@medic.gu.se
manipulation of gene activity impacts upon whole body physiology,
Project web-site: www.eurodiabesity.org/
endocrinology and phenotype. We will identify novel genes and
processes linked to the pathogenesis of diabesity and thereby find Key words: diabetes, obesity, metabolism, drug targets, dia-
potential molecular drug targets. Characterisation of those drug besity
targets, in particular by using molecular physiological studies and
integrative human biology, will be followed by target validation Partners
resulting in the identification of several novel, validated drug targets Prof.Astrup,Arne
for the treatment and prevention of diabesity. The Royal Veterinary & Agricultural University
Department of Human Nutrition, Rolighedsvej 30
Frederiksberg C, Denmark

32
DIABETES
Budapest, Hungary
Dr Barroso, Ins
Prof. Meister, Bjrn
The Wellcome Trust Sanger Institute
Department of Neuroscience, Karolinska Institute
The Wellcome Trust Genome Campus
Stockholm, Sweden
Hinxton, Cambridge, United Kingdom
Dr Mercer, Julian
Prof. Bloom, Steve Molecular Neuroendocrinology GroupAppetite and Energy
Department of Metabolic Medicine Balance Division, Rowett Research Institute, Bucksburn
Imperial College School of Medicine Aberdeen, United Kingdom
Hammersmith Hospital, London, United Kingdom Prof. Nolan, John
Dr Steuernagel,Arnd Metabolic Research Unit, Dept of Clinical Medicine
DeveloGen AG (Endocrinology)
Gttingen, Germany, Trinity College Dublin, St Jamess Hospital
Prof. Brning, Jens C Dublin, Ireland
Klinik II und Poliklinik fr Innere Medizin der Univesitt zu Prof. ORahilly, Steve
Kln University of Cambridge
Cologne, Germany Department of Clinical Biochemistry
Dr Cox, Roger D Addenbrookes Hospital
MRC Mammalian Genetics Unit, Medical Research Council Cambridge, United Kingdom
Harwell, Oxfordshire, United Kingdom Dr Pagotto, Uberto
Prof. Dieguez, Carlos Endocrine Unit
Universidad de Santiago de Compostela Dept. of Internal Medicine and Gastroenterology
Spain S.Orsola-Malpighi General Hospital
Prof. Enerbck, Sven Bologna, Italy
Medical Genetics, Department of Medical Biochemistry, Prof. Ricquier, Daniel
Gteborg University, Sweden Facult de Mdecine Necker-Enfants Malades
Paris, France
Prof. Ghigo, Ezio
Prof. Rohner-Jeanrenaud, Franoise
Division of Endocrinology and Metabolism,
Laboratory of Metabolic Research
Department of Internal Medicine,
Division of Endocrinology, Diabetology and Nutrition
University of Turin
Department of Medicine and of Morphology
Torino, Italy, Geneva, Switzerland
Dr Grosse, Johannes Prof. Seckl, Jonathan
Ingenium Pharmaceuticals AG, Munich, Germany, Molecular Medicine Centre
Dr Hager, Jorg Western General Hospital,
IntegraGen SA, 4, Edinburgh, United Kingdom
Evry, France Prof. Staels, Bart
Prof. Hebebrand, Johannes Institut Pasteur de Lille
Child and Adolescent Psychiatry of the Rheinischen Lille, France
Kliniken of the University of Duisburg-Essen, Prof.Treier, Mathias
Germany European Molecular Biology Laboratory
Prof. Jansson, John-Olov Developmental Biology Programme
Division of Endocrinology Heidelberg, Germany
Sahlgrenska Hospital, Gteborg University Prof.Tschp, Matthias
Sweden Dept. of Pharmacology, German Institute of Human
Prof. Leng, Gareth Nutrition
School of Biomedical and Clinical Laboratory Sciences Potsdam-Rehbrcke, Germany
University of Edinburgh College of Medicine
Edinburgh, United Kingdom Acronym: Diabesity
Prof. Liposits, Zsolt EC contribution: 11 700 000
Institute of Experimental Medicine Instrument: Integrated Project
Laboratory of Endocrine Neurobiology, Duration: 60 months

DIABETES EXGENESIS
Health benefits of exercise: identification of genes

and signalling pathways involved in effects of exercise on
insulin resistance, obesity and the metabolic syndrome
Summary capitalise on these new advances and begin the process of converting
them into new measures for prevention or treatment of disease.
Europe faces an epidemic of obesity, Type 2 diabetes and the metabolic Our proposal would establish a consortium that will execute an
syndrome. Obesity and insulin resistance, which can be regarded as Integrated Project on this topic in a truly multidisciplinary manner.
precursors of Type 2 diabetes,arise due to an imbalance between energy Our combined academic expertise ranges across molecular and cell
biology,use of animal models including transgenic mice,human muscle
intake and energy expenditure. Regular exercise, combined with an physiology, diabetic medicine, and human epidemiology, genetics and
improved diet, provides protection against, and an effective treatment interventional studies. Some of the methodologies we use include:
for, these conditions.This Integrated Project aims to provide a better
understanding of the molecular mechanisms involved in the protective
effects of exercise and a healthy diet,especially in terms of the signalling
pathways,and the changes in gene expression,involved.These improved
insights should allow the more rational design both of new
pharmaceutical interventions, and of policies designed to improve the
health of the population through improvements in lifestyle.
Problem
The European Union, like the rest of the developed and developing
world, is facing a major epidemic of three inter-related chronic
conditions, i.e.Type 2 diabetes, obesity and the metabolic syndrome.
Unless steps are taken to alleviate this crisis, the cost of treating the Studies of changes in protein localisation in live muscle fibres, using
long-term consequences of these conditions could overwhelm our fluorescent proteins
healthcare systems. Although genetic factors increase the risk of
developing these conditions, their rapid current global rise can only
be due to environmental factors. Obesity and insulin resistance, both
of which can be regarded as precursors of Type 2 diabetes, arise due 1) Molecular biological manipulation of signalling pathways in cultured
to an imbalance between energy intake and energy expenditure.This cells and in animal models, such as in vivo tranfection of DNA into
in turn may be due to two features of the modern urban lifestyle: mouse muscle (e.g. Fig. 1)
(i) frequent consumption of processed foods with high energy and 2) Metabolic studies of muscle during exercise and after exercise
low fibre content; training in male and female human volunteers, both in healthy
(ii) reduction in the amount of exercise taken due to changes in social subjects or those with Type 2 diabetes (e.g. Fig. 2)
and transport patterns. It is now well established that regular 3) Collection of clinical data, and DNA samples for genetic analysis,
exercise, combined with an improved diet, provides protection from families containing subjects with and without Type 2 diabetes,
against the development of these conditions, as well as a first line across large European regional populations (e.g. Fig. 3).
of treatment.
The consortium also includes two major European companies
involved in pharmaceutical and food production, and two small-to-
Aim medium enterprises involved in developing new technologies relevant
to our aims.
Recent major scientific advances (in which partners in this project
have played a prominent part) have begun to unravel the signalling
pathways,and changes in gene expression,in muscle and other tissues
through which the beneficial effects of regular exercise arise.The aim
of this proposal is to establish a major European consortium that will

34
DIABETES
Expected results These measures could take the form of new pharmaceutical
interventions based on the identification of signalling pathways or
1) Identify and delineate the intracellular signalling pathways that proteins responsible for the health benefits of exercise,or of new policies
mediate the effects of exercise in skeletal muscle of males and at local, national or EU level that produce beneficial changes in the
females. lifestyles of the population, especially in terms of diet and exercise.
2) Identify the mechanisms leading to release by muscle during
exercise of extracellular factors,such as cytokines,that affect insulin
resistance and transmit effects of exercise to other sites such as Coordinator
adipose tissue,the liver and endothelial cells,and study their action
at those sites. Prof. Hardie, D Grahame
Division of Molecular Physiology
3) Identify the signalling mechanisms stimulating release of fatty acids
and cytokines (adipokines) from adipose tissue during exercise and Faculty of Life Sciences
fasting. University of Dundee
4) Establish whether mutations affecting any of the signalling pathways Wellcome Trust Biocentre
involved in effects of exercise could predispose to Type 2 diabetes,
Dow Street
obesity or the metabolic syndrome in humans.
Dundee DD1 5EH, Scotland, United Kingdom
5) Delineate patterns of expression of genes and proteins in humans
at risk of developing Type 2 diabetes and in cohorts of monozygotic Phone: +44 1382 344253
and dizygotic twins of known health status. Fax: +44 1382 345783
6) Validate potential new drug targets identified during the research, Email: d.g.hardie@dundee.ac.uk
using small molecule inhibitors or activators, expression of Project web-site:
constitutively active or dominant negative mutants, siRNA techno- http://www.dundee.ac.uk/lifesciences/exgenesis/
logy, or gene targeting in mice.
Key words: exercise, genes, signalling pathways, diabetes,
7) Develop technologies that enable screening of drugs using obesity, metabolic syndrome
immortalised human muscle cells, and more effective long-term
monitoring of human physical activity and cardiac function.
Partners
5 Denmark
1 Belgium
2 France
1 Finland
3 Sweden
5 United Kingdom
2 Spain
1 Switzerland
1 Czech Republic
1 The Nederlands
1 Italy
1 Germany
Metabolic studies during exercise in female and male volunteers 1 Poland
Acronym: EXGENESIS
Potential applications Project number: LSHM-CT-2004-005272
New insights gained in this project will provide an evidence base to allow Instrument: Integrated Project
Duration: 60 months
the more rational design of measures aimed at reducing the large burden Starting date: 01/01/2005
of Type 2 diabetes,obesity and the metabolic syndrome in the population.

DIABETES EUGENE2
European network on functional genomics

of Type 2 Diabetes
Summary bringing together specific expertise in the required areas of cell-
and molecular biology, rodent models, biology of target organs for
EUGENE2 is a Network of Excellence focused on functional genomics, insulin action (skeletal muscles, adipose tissue and liver) as well as
combined access to unique patient populations allowing functional
genomics, proteomics and bioinformatics to unravel the complex
genomic and genetic studies. The establishment of common
pathogenesis of Type 2 diabetes and the specific role of the skeletal research protocols, technical platforms and databases will promote
muscle, fat and the liver. This involves the dedication and the durable and sustainable integration.The increased critical mass and
the joint efforts of scientists with complementary expertise will
development of common research infrastructures in human and rodent
allow EUGENE2 to advance the current state of the art and provide
genomics and bioinformatics combined with cohesive research efforts new insights into the pathogenesis of Type 2 diabetes and to
in proteomics, transcriptional regulation, insulin signalling and action in improve existing therapy.
the target tissues. A concerted effort in applying functional genomic
approaches in target cells,rodents,and humans will generate information Aim
necessary to make advances in health care,pharmaceutical development Many steps are taken to strengthen European diabetes research and to
and public health policies. reduce fragmentation.These include indirect integrating activities based
on jointly executed research (JER), and direct integrating activities:
Problem coordinated programming of research in order to strengthen the

complementarity of the participants
Type 2 diabetes is a complex polygenic disease where genetic
sharing of common research tools and platforms
susceptibility interacts with environmental factors.An early event in
the development of Type 2 diabetes is insulin resistance, i.e., an joint use of infrastructures
impaired effect of insulin in the target tissues (muscle, adipose tissue exchange of staff and training programmes
and liver).
integrated management of knowledge and intellectual property and
Although the metabolism and function of all these tissues are altered implementation of a Joint Strategy for Immaterial Property rights.
in the diabetic state, it is currently
unknown if, and to what extent, these
changes are secondary to the diabetic state
or if they are initiating events in the
development of the disease.
To comprehensively study the
pathogenesis of as complex a disease as
Type 2 diabetes requires a broad array of
experimental technologies, access to
different experimental models (cells and
animals), expertise in muscle, adipose
tissue and liver biology as well as well-
characterised human populations with the
disease and genetically predisposed
individuals who have not yet developed
Type 2 diabetes. Consequently, no single
research group in Europe has the capacity
to comprehensively study such a
complicated disease. The existing
fragmentation of diabetes research in
Europe is an important obstacle to
success.
EUGENE2 integrates top scientists in The Joint Programme of Activities of EUGENE 2
diabetes research in Europe, thereby

36
DIABETES
Graphical presentation of the research components of EUGENE 2 and their relationships
reinforcement of electronic information and communication Expected results

networks.
1. Promoting integration through the establishment of common
The jointly executed research is focused on generating new knowledge
research platforms for bioinformatics, novel reagents and cell lines,
to fill existing gaps as well as to develop platforms for common use.
RNA and DNA samples, proteomics and engineering and
A JER programme is, by definition, an instrument for integration. phenotyping animal models.
Although intensive research has been focused on the genetics of Type 2. Jointly executed research to identify novel genes related to Type 2
2 diabetes during many years,major genes contributing to this disease diabetes. Success in this endeavour will have major health
remain largely unknown. implications for both the diagnosis and treatment of Type 2 diabetes.
Each partner in EUGENE2 will bring unique expertise to the 3. Characterising the function of genes related to insulin resistance
project together with particular models or experimental and Type 2 diabetes as well as their genomic associations and/or
techniques such as: linkage.
unique patient populations and phenotyping procedures combined 4. Establishing joint training programmes and scientist exchange
with functional genomics and/or genetics programmes to strengthen European research expertise in this field.
unique animal models and their characterisation 5. Strengthening the European pharmaceutical and biotechnology
signal transduction and engineered cell models industries through research collaboration and policy for protection
of knowledge.
peptide synthesis and drug discovery.

DIABETES
Coordinator Karolinska Institutet

Prof. Smith, Ulf Section of Integrative Physiology
Lundberg Lfaboratory for Diabetes Research, Dept. of Dept. of Surgical Science
Internal Medicine, Sahlgrenska Academy at Gteborg
Stockholm, Sweden
University
Prof. Joost, Hans-Georg
413 45 Gteborg, Sweden
Dept. of Pharmacology
Phone: +46 31 3421104
German Institute of Human Nutrition
Fax: +46 31 829138
Potsdam-Rehbruecke
Email: ulf.smith@medic.gu.se
Potsdam-Rehbrcke, Germany
Project web-site: www.eugene2.com (to be
Prof. Beguinot, Francesco
established).
Dipartimento di Biologia e Patologia Cellulare
Key words: diabetes, insulin resistance, cardiovascular
e Molecolare (DBPCM)
disease, adipose tissue, liver, skeletal muscles
II Facolt di Medicina
Partners
Naples, Italy
Prof. Laakso, Markku
Prof.Van Obberghen, Emmanuel
Department of Medicine
Inserm Unit 145 Facult de Mdecine
University of Kuopio
Nice, France
Kuopio, Finland
Prof.Auwerx, Johan
Prof. Hring, Hans-Ulrich
Institut Clinique de la Souris
Medizinische Universittsklinik
Illkirch, France
Tbingen, Germany
Prof. Bosch, Fatima
Prof. Sesti, Giorgio
Center of Animal Biotechnology and Gene
Department of Experimental and Clinical Medicine Therapy (CBATEG)
University Magna Graecia of Catanzaro Universitat Autnoma de Barcelona (UAB)
Catanzaro, Italy Bellaterra, Spain
Prof. ORahilly, Stephen Director Levens, Nigel
Clinical Biochemistry Biovitrum AB,
Addenbrooks Hospital Stockholm, Sweden
Cambridge, United Kingdom
Prof. Pedersen, Oluf
Acronym: EUGENE2
Steno Diabetes Center Project number: LSHM-CT-2004-512013
Gentofte, Denmark Instrument: Network of Excellence
Duration: 48 months
Prof. Zierath, Juleen R Starting date: 01/11/2004

38
TONECA DIABETES
Coordination action on the aetiology, pathology

and prediction of Type 1 diabetes in Europe
Summary This will be achieved in particular through
Coordination of common clinical and experimental studies and
Type 1 diabetes mellitus (T1DM) imposes a heavy burden of morbidity experiments on T1DM.
and premature death on more than 2 million inhabitants in Europe.To
Organisation of conferences,workshops and expert group meetings.
identify new targets for prevention, diagnosis and treatment of T1DM,
Organisation of the exchange of personnel.
greater understanding of its aetiology and pathology is crucial. This
Exchange and dissemination of ethical principles and good practice
requires the elucidation of the cellular and molecular mechanisms
in clinical and experimental diabetes research through setting up
responsible for T1DM through bringing together leading European common information systems and expert groups.
centres of expertise in the field of clinical and experimental T1DM Running of a central network resource for collection,quality control,
research.The capabilities of the European groups participating in this storage and dissemination of biological materials.
coordination action (CA) provide the required technical skills and
innovative advances. European diabetes research expertise in T1DM as Expected results
assembled in this CA proposal will enable the coordination of RTD
The results of this CA will be:
projects which are already in receipt of funding for the research part.
Increased knowledge and new expertise in T1DM research.
The research topics to be coordinated in this CA deal with (a) molecular
Education of young and advanced scientists in T1DM research.
mechanisms of beta cell death and signalling pathways of apoptosis in
T1DM; (b) the impact of environmental factors upon the genetically Exploitation of the acquired knowledge for the development of new
therapeutical concepts for the prevention, diagnosis and treatment
based regulation and progression of T1DM; (c) the use of established of T1DM.
and new animal models to unravel the molecular mechanisms of the
The new knowledge achieved through this CA will be, in particular,
aetiology and pathology of T1DM; (d) the role of the cellular immune a better understanding of:
system in the pathogenesis of T1DM.The financial support for this CA
Molecular mechanisms of immune mediated beta cell death and
will allow the running of the coordination activities.This will make it signalling pathways of apoptosis in T1DM, oxidative stress and
possible to better understand the underlying causes of T1DM with the cytokines.
aim of identifying targets for prevention, diagnosis and treatment. Impact of environmental factors upon the genetically based
regulation and progression of T1DM.
Problem Role of the cellular immune system in the pathogenesis of T1DM,
the role of the T cells and the identification of triggering factors of
Type 1 diabetes mellitus (T1DM) is a complex multigenic disease with the autoimmune reaction.
a large socio-economic impact. It is the most frequent metabolic
disease in children and affects around two million children and adults Both in human studies and through the use of established and new
in Europe.In many areas of Europe the incidence of T1DM is increasing T1DM animal models, unraveling the molecular mechanisms of the
and affecting children at a progressively younger age. aetiology and pathology of T1DM.
Aim Potential applications

The aim of this CA is to use advanced genomics to detect triggers Due to the increasing incidence of T1DM in Europe there is an urgent
of autoimmunity and regulators of progression as well as mechanisms need for the development of new preventive and curative therapies
of cell death in well-characterised patient cohorts and experimental of this disease. The activities of this Coordination Action will allow
model systems with the aim of identifying targets for prevention, the identification of new targets for prevention, diagnosis and
diagnosis and treatment. treatment of T1DM. This understanding will help to provide the
rational basis for the development of new pharmaceutical and gene
To achieve this aim the CA will promote and support the networking therapies against this serious disease.
and coordination of research and innovation activities in the field of
T1DM in Europe.

DIABETES
Coordinator College Dublin, Ireland

INSERM Unit 457, Robert Debr Hospital, Paris, France
Lenzen, Sigurd
Development & Reproductive Biology, Biomedicum
Institute of Clinical Biochemistry
Helsinki, Finland
Hannover Medical School
Steno Diabetes Centre, Gentofte, Denmark
30625 Hannover, Germany
Department of Immunohaematology & Blood Tranfusion,
Phone: + 49 511 532 6525 Leiden University Medical Centre, the Netherlands
Fax: + 49 511 532 3584 Department of Endocrinology and Metabolism, University
of Pisa, Italy
E-mail: Lenzen.Sigurd@MH-Hannover.de
Enterovirus Laboratory, National Public Health Institute,
Project web-site:
Helsinki, Finland
http://www.mhhannover.de/institute/clinbiochemistry/toneca
LEGENDO, UZ Gasthuisberg O&N, Leuven, Belgium
Key words: Type 1 diabetes, beta cell apoptosis,
autoantibodies, immunology, animal models Department Medical Biochemistry, Ernst-Moritz-Arndt-
University, Germany
Partners Endocrine Unit, Hospital Universitari de Bellvitge,
Barcelona, Spain
Department of Pharmaceutical Sciences, Aston
University, United Kingdom Dept of Medical Cell Biology, Uppsala University, Sweden
School of Biomedical Sciences, University of Ulster, Institute of Biomedical & Clinical Science, Peninsula
United Kingdom Medical School, United Kingdom
CeeD, Centre europen dtude du Diabte, France

Acronym: TONECA
Diabetes & Metabolism Unit, Medical School, Southmead Project number: LSHM-CT-2004-503245
Hospital, Bristol, United Kingdom EC contribution: 1 000 000
Instrument: Coordination Action
School of Pharmacy & Biomolecular Sciences, United Duration: 48 months
Kingdom Starting date: 01/06/2004
Endocrinology & Diabetes Unit, University of Barcelona

Medical School, Spain
Immunology of Diabetes Unit, San Raffaele Scientific
Institute, Milan, Italy
Pharmacy and Biomolecular Sciences, University of
Brighton, United Kingdom
Dept. of Internal Medicine Endocrinology, University of
Siena, Italy
Laboratory of Pharmacodynamics, Universit Libre de
Bruxelles, Belgium
Laboratory of Experimental Medicine, Universite Libre de
Bruxelles, Belgium
GKT School of Biomedical Sciences, Kings College
London, United Kingdom
Department of Molecular Medicine, Karolinska Hospital,
Stockholm, Sweden
Childrens Hospital, University of Tbingen, Germany
Lilly Research Laboratories, Hamburg, Germany
Department of Biochemistry Institution, University

40
IMMIDIAB DIABETES
Genetic susceptibility for Type 2 diabetes

and obesity among immigrants in Europe:
Prevention and treatment
Summary information may help in understanding the pathophysiology of T2DM
in other population and thereby methods of treatment and prevention
The epidemiology of Type 2 diabetes and its complications vary in general.Since the ethnic mix of the European population is changing
significantly between ethnic groups. Immigrants in western Europe, rapidly,the identification of the mechanism involved in Type 2 diabetes
particularly from the South-Asian countries, appear to represent the is also important for the other ethnic groups.
epidemic challenge to understand the genetic predisposition and its
There is a need to organize cohesive efforts from various specialties
interfaces with the adaptability to new environmental conditions for
like obesity and T2DM in genetics, bioinformatics, cell biology, clinics,
the development of Type 2 diabetes mellitus (T2DM). Communities
epidemiology, and prevention.
undergoing transitory lifestyles offer an ideal opportunity to gain
insight to the patterns of genetic predispositions and their complex
interplay with lifestyle that may explain the increasing prevalence of
Problem
obesity and T2DM in Europe and the rest of the world today. To understand the genetic predisposition and its interfaces with the
adaptability to new environmental conditions for the development of
The relationships between the conditions like obesity, T2DM and Type 2 diabetes mellitus.
insulin resistance and impaired insulin secretion are complex. They Complex interplay with the lifestyles that may explain the increasing
may have some common genetic traits and endocrinological features prevalence of obesity and T2DM in Europe and the rest of the world
today.
but the pathophysiology responsible for the development of
hyperglycaemia in Type 2 diabetes is yet to be established. Obesity To explain the pathophysiology responsible for the development of
hyperglycaemia in T2DM.
stands out as a risk factor for T2DM, but lean Type 2 diabetes was
To provide clues to more effective treatment and prevention of
also observed in India and Bangladesh. Recent observations of
diabetes and obesity.
extremely lean, lipoatrophic models have revealed a similar
predisposition to developing diabetes as with those with increased
Aim
adiposity. Further investigations are needed in the adipose tissue and
Create a network of specialists of obesity and T2DM in genetics,
its dysfunction in the pathogenesis of diabetes.
bioinformatics and cell biology, clinics, epidemiology and prevention
Proteomics are necessary in these investigations. The thrifty through three workshops,two training program and one international
conference:
phenotype hypothesis, introduced by Hales and Barker in 1992,
1. to train new researchers;
proposed the concept that environmental factors acting in early life
might influence later risk of Type 2 diabetes.This may obviously have 2. to conduct a small-scale genetic study of obesity and T2DM and of
lifestyle in available immigrant populations in Oslo, London and
played a role in the increased development of Type 2 diabetes among Helsinki (funded outside the present project);
immigrants to Europe. Reduction of obesity is the core point in the
3. to contribute to develop bioinformatics;
treatment of diabetes in all ethnic groups. Reduced calorie intake and
4. to plan a bigger study of genetics and lifestyle across ethnicity.
increased physical activity are the main treatment issues for both the
conditions.Individualisation of treatment may be enhanced by further
studies in genetic epidemiology.
The understanding of the etiology and mechanism causing increased

hyperglycaemia in this population will provide clues to more effective
treatment and prevention of diabetes and obesity. Furthermore, the

DIABETES
Expected results
Coordinator
Reports and review articles from the workshops will be made.Two
training courses for new researchers will be arranged.At the end of Prof. Claussen, Bjrgulf
the period, an international conference will be held. University of Oslo
Three workshops will address different aspects of the mentioned Pb. 1130-Blindern
conditions. Reports and review articles will be made in order to
provide new information and to identify needs and develop protocols 0318 Oslo, Norway
accordingly for future research. Phone +47 2 285 0614
The current project will contribute to better identifications of Fax: +47 2 285 0610
different subtypes, first, by summing up present knowledge, and
second, by planning and making concerted research on genetics, Email: bjorgulf.claussen@medisin.uio.no
epidemiology and clinical conditions together with obesity. Project web-site:
www.med.uio.no/iasam/arbeidstrygd/immidiab
Potential applications Key words: Type 2 diabetes, obesity, genetics, lifestyle
The overall aim is to provide qualified suggestions to policymakers
and to different interest groups for the development of prevention Partners
and treatment strategies for people at risk across different
genotypes, clinical diagnoses, lifestyles and cultures. The ultimate University of Rome TorVergata, Italy
objective for the network is to plan a bigger study of genetics and kBioscience Ltd, Cambridge, United Kingdom
lifestyle across ethnicity in Europe. In order to implement the plan
we must be able to bridge the fragmented research and form a The European Association for the Study of Diabetes,
cohesive approach. Dusseldorf, Germany
Diabetic Association of Bangladesh
Diabetic Association of Pakistan
University of Malmo, Sweden
London University, United Kingdom
University of Helsinki, Finland
WHO collaborating Centre on Diabetes in India
University of Geneva, Switzerland
Acronym: IMMIDIAB
Duration: 18 months

42
Rare diseases
Eumitocombat 44
Euroglycanet 47
GENESKIN 49
EuroWilson 52
PWS 56
EUGINDAT 58
EURAPS 60
AUTOROME 62
Orphanplatform 64
RARE DISEASES Eumitocombat
Rational treatment strategies combating mitochondrial

oxidative phosphorylation disorders
Summary The contribution of mtDNA mutations to human disease was already

recognised in the late 1980s,when maternally inherited point mutations,
Defects in the mitochondrial oxidative phosphorylation (OXPHOS) as well as clonally inherited mtDNA deletions arising spontaneously
during development,were found to be associated with rare neurological
system,the principal circuit for cellular energy production,lead to often
syndromes.Since then,three further advances in our understanding have
fatal, multi-system disorders affecting organs and tissues with a high- greatly expanded the field of mitochondrial OXPHOS disorders:
energy demand. The Eumitocombat consortium, consisting of 12 The mtDNA genotype has been found to be a significant contributor
partners and encompassing 21 scientific groups from nine different to a range of relatively common,complex or heterogeneous disorders,
countries, aims to integrate and extend knowledge on basic aspects of including diabetes, sensorineural deafness and cardiomyopathy.
OXPHOS biology and the patho-biological cascades underlying Many nuclear genes that play roles in mtDNA maintenance or
OXPHOS disease manifestation in humans.All of the major European expression have also been found to be involved in disease, including
some disorders whose mitochondrial basis was not previously
groups active in the forefront of OXPHOS research will participate in recognised.
the project, including the Nobel Prize laureate, Sir John Walker. The
More controversially, the demonstrable alterations to mtDNA
Eumitocombat project will reinforce Europe as the international leader during aging have given rise to the idea that somatic mutation of
in the development of treatments capable of combating these disorders. mtDNA as a result of oxidative damage may play a functionally
significant role in the degenerative processes of aging itself.
To this end we will:
Despite a relative explosion of knowledge in the past decade,
integrate clinical and model-system expertise mitochondrial OXPHOS disease remains essentially intractable.
Furthermore, it is also devastating in its impact on patients and their
characterise important genes and proteins involved in the formation
families.
and regulation of the OXPHOS-system
For all these reasons, new knowledge about mtDNA, about the
study the network of components involved in cellular energy OXPHOS system and its biogenesis, and about the cellular,
developmental and physiological consequences of OXPHOS
metabolism by functional genomics
dysfunction, is urgently needed, in order to establish a feasible
develop more efficient genetic and protein (mutation) screening therapeutic strategy to treat these debilitating disorders.
methods
evaluate the cellular alterations/adaptations of these defects in

specified cells, tissues, models and humans
develop methods to target and test therapeutic agents to specific

(sub)cellular locations.
Problem
Mitochondrial DNA (mtDNA), and the machinery that maintains and
expresses it, constitute a partially autonomous genetic system within
eukaryotic cells. Present in hundreds or even thousands of copies per
cell, with the possibility of heteroplasmy (mixtures of mtDNA of
different genotypes), maternal inheritance, and dependence upon
hundreds of diverse nuclear genes for its function, mtDNA is also
subject to unique rules.
Moreover,the functions that it encodes -13 key subunits of the OXPHOS
complexes,plus the translational RNAs needed to synthesise them - are
essential for life, being at the core of energy metabolism.Therefore, it is Model of human complex I, with the various subunits
not surprising that the genetic fitness of mtDNA is crucial for health.

44
RARE DISEASES
4. to apply the knowledge gathered from such approaches to the

rational design and testing of therapeutic agents and manipulations
to ameliorate the manifestations of OXPHOS disease.
Expected results
Arising from the work on the natural history of OXPHOS disease, a
series of workshops will be organised,leading finally to the elaboration
of guidelines for clinical management of OXPHOS patients and the
evidence-based nosological reassessment of the entire field of
OXPHOS disease. News about progress towards the objectives will
be published and updated annually. Dissemination will be via existing
clinical and patient organisation networks in the format of annual
electronic newsletters.
Major achievements of the project will be pre-published on the
Eumitocombat website. All scientific results will be submitted for
publication in high quality, peer-reviewed journals.
During the lifetime of the project it is expected to elucidate novel
gene defects causing OXPHOS disease, using linkage analysis. New
tools for diagnosis of OXPHOS disease will be developed, based on
retrovirus- and baculovirus-mediated complementation. New animal
models are expected to be generated during the project. Procedures
and tools for analysing the mtDNA maintenance machinery will be
Calcium signal following loading with Rhod-2 and the hormone
developed, including an improved procedure for the isolation of
bradykinine in a control human fibroblast cell line mitochondrial nucleoids. Each of the new treatment compounds to
be developed will be characterised and tested in vitro. In the final
conference/workshop organised by Eumitocombat the state of
mitochondrial research will be evaluated, focusing on the evaluation
of new treatment strategies at the patient level, arising from the
Aim outcomes of the project.
The projects main goals are to obtain a detailed understanding of the

clinical and pathobiological consequences of OXPHOS disease in Potential applications
order to develop new treatment strategies. Efforts will be focused on The project sets out an ambitious, integrated research programme
complex I, complex IV, mitochondrial DNA maintenance and to build on the achievements described in the preceding section.
mitochondrial protein synthesis disturbances.The major objectives, Using many of the same tools and models, innovative, functional
around which the scientific and technological work is structured,apply genomic technologies will be applied to define the cellular and
to each of these disease categories: organismal consequences of OXPHOS dysfunction and reveal
1. to understand properly the natural history of the disease,its clinical pathways and molecules of potential value as drug targets. A
manifestations and their time-course,and the relationship between definitive classification of OXPHOS disorders will be elaborated,
genotype and phenotype. The eventual goal will be to provide using systematic clinical criteria and a rigorous application of
routine and rapid diagnosis, which will form the rational basis for genetics. Novel techniques will be developed for rapid diagnosis of
future therapy mitochondrial disease based on functional complementation.The full
panoply of genomic tools to identify the remaining key loci involved
2. to elucidate the pathophysiology of the disease by the analysis of in OXPHOS disease will be applied. The consortium will combine
biological models, thus revealing potential new therapeutic their existing OXPHOS disease models and promising
strategies or targets pharmacological agents to test out therapeutic strategies, in
3. to characterise in detail the cellular machinery primarily affected collaboration with SME partners.
by the disease process (i.e. complexes I and IV, the components The aim for the four years of the project is to provide a platform for
involved in their assembly, and the machinery of mtDNA the development of effective treatments for OXPHOS disease that
maintenance and expression). A complete understanding of basic can have a real and sustained impact on the lives of patients and their
biological processes underlying OXPHOS will lead to the families.
discovery of novel drug targets

45
RARE DISEASES
Coordinator Dr. Josef Houstek
Prof. Smeitink, Jan Institute of Physiology, Academy of Sciences of the Czech

Republic
Stichting Katholieke Universiteit
Prof. Jiri Zeman
University Medical Centre Nijmegen
Charles University, 1st Faculty of Medicine, Prague,
Nijmegen Center for Mitochondrial Disorders Czech Republic
Department of Paediatrics Prof. Howard Jacobs
Geert Grooteplein 10 University of Tampere, Institute of Medical Technology,
P.O. Box 9101 Finland
6500 HB Nijmegen,The Netherlands Prof. Robert Lightowlers, Dr. Douglas Turnbull
Phone: +31 24 361 4430 University of Newcastle Upon Tyne, Department of

Neurology, Newcastle upon Tyne, United Kingdom
Fax: +31 24 361 6428
Prof. Ferdinando Palmieri, Prof. Luigi Palmieri
Project web-site: http://www.eumitocombat.org
University of Bari, Department of Pharmaco-Biology,
Key words: rare diseases, inborn errors of energy Bari, Italy
metabolism, orphan diseases
Dr. Agns Rtig, Dr. Pierre Rustin
Partners Institut National de la Sant et de la Recherche Mdicale,

Paris, France
Dr. Peer Bork
Dr. Massimo Zeviani
European Molecular Biology Laboratory, Structural and
Istituto Nazionale Neurologico C. Besta, Milano, Italy
Computational biology, Heidelberg, Germany
Dr. Jos A. Enriquez
University of Zaragoza, Department of Biochemistry Acronym: Eumitocombat
and Molecular Cell Biology, Spain Project number: LSHM-CT-2004-503116
Dr. Nib-Gran Larsson, Dr. Claes Gustafsson Instrument: Integrated Project
Duration: 48 months
Karolinska Institute, Sweden Starting date: 01/07/2004
Prof. Sir John Walker, Dr. Ian Holt,

Dr. Michael Murphy
Medical Research Council, Department MRC-Dunn
Human Nutrition Unit, Cambridge, United Kingdom

46
Euroglycanet RARE DISEASES
Congenital disorders of glycosylation: a European

network for theadvancement of research, diagnosis
and treatment of a growing group of rare disorders
Summary Problem
The congenital disorders of glycosylation (CDG) are an emerging Glycosylation is the most complex type of biomolecule modification
occurring in living organisms. Given this complexity and the large
group of inborn errors of metabolism. CDG are typically multi- number of enzymatic steps involved in protein glycosylation, it is
system diseases, with a broad spectrum including mental retardation anticipated that many disorders are still unrecognised. Also,it is a rare
and severe developmental delay, structural abnormalities of the disease, for which the diagnostic, clinical and research expertise is
limited to a few centres in Europe.
central nervous system and cardiac defects, malformations,
hormonal deregulation and coagulation problems, peripheral Most patients with CDG can be diagnosed by relatively simple
laboratory tests that detect abnormal glycosylation in serum proteins.
neuropathies, etc. There is a high morbidity and a significant In contrast, the identification of the underlying defect often requires
mortality. expert enzymatic, biochemical or molecular investigations. It is at this
stage that the expert diagnostic services, offered by the different
Euroglycanet will promote early diagnosis by offering the diagnostic laboratories involved in the network, are playing an important role in
tools for screening as well as for expert analysis and by raising the diagnosis of CDG.
awareness. It will integrate research activities in the field, and work
towards the development of therapies for CDG and related
disorders.
To fulfil these aims, Euroglycanet will 1) develop and share effective

tools for early and expert diagnosis; 2) manage a sample flow
through the different laboratories involved in this activity and 3) Distribution of
Partners of the
maintain a database, accessible through Internet and a public
Euroglycanet project
website. accross Europe
Euroglycanet will also raise awareness by 4) providing information
to the public and to physicians and other professionals, and by 5)
offering training to expert clinicians and researchers in the field.
To foster research it will select interesting cases for research and 6)

establish an international research forum, including one international
congress,where clinical and basic scientists will meet.The coordinated Aim
diagnostic and research activities include a.o. applications of DNA- Euroglycanet will bring together all the leading European groups
arrays, 2-D gels, mass spectrometry and capillary electrophoresis for with an interest and expertise in CDG and related syndromes.The
aim is to co-ordinate research and expert diagnostic activities, and
the study of glycoprotein synthesis and defects. 7) The network will to promote awareness and knowledge of this group of diseases.
promote collaborations with companies for the development of The project also aims at providing the basic diagnostic tools for
therapeutics. The integration of clinical and basic research groups physicians by establishing referral laboratories in the European
centers that collaborate with Euroglycanet.
within the network is a strong advantage in this respect.
It will integrate research activities in the field, and work towards
Euroglycanet will also 8) increase quality and standardisation by the development of therapies for CDG and related disorders.
offering QA schemes and 9) spread and promote access to These research activities are grafted onto a central database and
patient sample repository.The samples circulate along the different
diagnostic services by installing additional referral centres in
expert laboratories a principle which was coined carousel
different European countries, including the new member states. testing.

47
RARE DISEASES
Expected results
1. unite the leading European groups into a multidisciplinary network Coordinator
2. exploit novel diagnostic and scientific tools Prof. Matthijs, Gert
Centre for Human Genetics, University of Leuven,
3. continue the patient database and specific mutation databases
Gasthuisberg, Herestraat 49
4. coordinate and expand a network of specialised centres that
3000 Leuven, Belgium
provide early and accurate diagnosis
Phone: +32 16 34 60 70
5. develop new therapeutic strategies
Fax: + 32 16 34 60 60
6. raise awareness Email: gert.matthijs@med.kuleuven.ac.be
7. training of young, expert clinicians and scientist and education of Project web-site: www.euroglycanet.org
other specialists Key words: early diagnosis, patient database, awareness,
8. quality assurance, quality assessment and standardisation training and education
Potential applications Partners

Assistance Publique-Hpitaux de Paris, France
Euroglycanet has identified national referral laboratories that will
assume a role of satellites or outstations for the first-line analysis University of Nijmegen, the Netherlands
and dispatch of samples. All satellite laboratories from the network University of Zurich, Switzerland
will be provided with the same technical equipment and standard test Hospital Sant Joan de Du / IBC, Spain
protocols.
Institute of Child Health, London, United Kingdom
The network will provide access to (early) diagnostics at a pan- University of Gttingen, Biochemie 2, Germany
European scale; it is committed to training and education, directly
Eidgenssische Hochschule, Zurich, Switzerland
coupled to clinical and basic research. These activities will affect
quality of life of the patients with CDG, and their families. A Christian de Duve Institute of Cellular Pathology, Belgium
definitive diagnosis is one of the most important things for families INSERM U504,Villejuif, France
with an affected child. Institute of Child Health,Athens, Greece
The network will try to consolidate the European lead on clinical University of Catania, Italy
and fundamental research into this group of rare diseases. The University of Porto, Portugal
close interaction between expert clinicians and specialised
Childrens Memorial Health Institute,Warsaw, Poland
researchers, together with the centrally monitored carousel
testing, could become a model for the organisation and integration University Hospital of Copenhagen, Denmark
of clinical and basic research for other rare diseases, in and beyond Charles University, Prague, Czech Republic
the metabolic field. Higher Medical School, Sofia, Bulgaria
Universidad Autonoma de Madrid, Spain
Hadassah and Shaare Zedek MC, Jerusalem, Israel
Rambam Medical Center, Haifa, Israel
Department of Paediatrics, Zagreb, Croatia
Institute of Chemistry and Technology of Polymers,
Catania, Italy
Orphan Europe, Paris, France
CLIMB, Crewe, United Kingdom
Universittskinderklinik, Heidelberg, Germany
Acronym: Euroglycanet
Duration: 48 months

48
GENESKIN RARE DISEASES
Rare genetic skin diseases: advancing diagnosis,

management and awareness through a European network
Summary Problem
Genetic skin diseases comprise almost 300 rare but often severe Genetic skin disorders encompass almost 300 different diseases and
syndromes, most of which are severely disabling or life threatening
and even life-threatening diseases and syndromes. Despite recent and have a major impact on health care services and personnel.The
identification of causative genes in a number of these disorders, number and rarity of these disorders (prevalence between 1:6 000
the molecular bases of several others are still unknown, and often and <1:500 000 for each condition) hamper single-centre (or country)
studies aimed at their characterisation and cure. Despite the great
the function of the identified disease-gene products remains an
progress of the last decade, the molecular basis of several of these
unsolved mystery. In addition, disease number and rarity impair diseases is still unknown, and in many cases the function of the known
proper management, and no curative therapy is available. By disease-gene products remains an unsolved mystery.Furthermore,no
curative therapy is at present available for any form of genetic skin
bringing together clinicians, researchers and patient associations,
disease and pharmaceutical companies have limited or no interest in
GENESKIN aims to generate accessible knowledge and improve developing diagnostic and therapeutic strategies for these orphan
health care service structures for affected people.The focus is on diseases.A significant logistical problem is that only a few centres in
five major disease categories: epithelial adhesion disorders, Europe are in a position to try to deal with groups of these diseases
and even then their expertise is limited to just a few specific
keratinisation disorders, ectodermal dysplasias, connective tissue conditions. Thus, expert knowledge for clinical and molecular
diseases, DNA repair disorders. For each group, a clinical and diagnosis, for management and innovative therapy is isolated and
laboratory network will generate and disseminate: 1) a list of scattered in an often uncoordinated way throughout Europe. As a
result patients experience significant difficulties in finding experts and
reference centres with services offered, 2) diagnostic question-
multidisciplinary healthcare teams specialised in clinical and
naires/protocols, 3) gene cards, mutation database, diagnostic molecular diagnosis, able to offer high quality disease management.
reagent lists, and ongoing clinical trial list. The research topics to This situation can only be overcome by a European mobilisation of
activities and resources, most effectively through a European
be co-ordinated in GENESKIN deal with: i) improved early post-
consortium that will facilitate development of substantially improved
natal and pre-natal diagnosis by novel immunohistochemical/ and cost-effective health care services.
biochemical and molecular tests, ii) identification of new
genes involved in genetic skin diseases by collecting a
sizeable number of biological samples, iii) definition of
genotype-phenotype correlation and characterisation of
newly identified gene product functions by creation of
a sample databank. Knowledge dissemination and
improved management will also be ensured through the
organisation of involved personnel training. Finally, pan-
European communication among patients organisations,
ethics committees, physicians and scientists will be
promoted.The information regarding clinical/diagnostic
protocols/lists, diagnostic and research tools and
communication among different groups will be
integrated and disseminated through a dedicated
website.
Schematic representation of the GENESKIN project

49
RARE DISEASES
Aim function findings into clinical applications that are relevant to accurate,
rapid and early diagnosis,molecular and prenatal testing,and to foster
The present project arises as a joint effort of European scientists and implementation of clinical trials. In particular, the multidisciplinary
clinicians, with the direct involvement of patients associations, to synergistic efforts of investigators and clinicians,in close collaboration
establish a consortium of groups engaged in providing a critical mass with patient associations, will allow:
of patients and research tools in the fields of inherited skin diseases,
the establishment of a European task force for the study of these
including diseases predisposing to skin cancer. To this regard, the
rare disorders at fundamental and clinical levels;
projects main objectives are:
the rapid translation of the novel knowledge and diagnostic tools
to create a European clinical and diagnostic network for five major
from the bench to the bedside, resulting in an improved diagnosis
groups of genetic skin diseases,namely epithelial adhesion disorders,
and management of these disorders at European and national scale;
keratinisation disorders, ectodermal dysplasias, connective tissue
diseases, and DNA repair diseases the augmentation of an early and accurate pre- and post-natal
diagnosis, which is crucial for prognosis definition and proper
to integrate, test and validate diagnostic and research tools for the
management, and is beneficial for the psychological well-being of
above-mentioned disease groups
patients and families who do not feel well living in diagnostic
to promote training on clinical, diagnostic and management aspects uncertainty and insecurity;
of specific disease groups
easier access for patients to clinical trials and in general earlier and
to promote pan-European communication pathways among patients proper management leading to an increase of the quality of life of
organisations, ethics committees, physicians and scientists. the patients, and improvement of the clinical course of the disease.
This will reflect positively over the duration of life expectancy and
medical costs.
Expected results
In addition, close co-operation of physicians and scientists with public
a web-based informatics platform that, for each of the five non-medical groups,i.e.patients organisations and ethics committees
categories of diseases listed above, will contain: will contribute to:
1) a list of reference centres with clinical/diagnostic services offered; developing and maintaining an equal dialogue among these different
2) diagnostic questionnaires/protocols/check-lists; parts;
3) gene cards and mutation database; patient-specific needs being continuously part of medical and/or
scientific decisions, in agreement with ethical values;
4) lists of available diagnostic reagents;
further raising public awareness about rare diseases,fulfilling societal
5) disease-related web-sites and ongoing clinical trials; goals.
6) recent updates in the proper field.
for selected diseases:
1) standardised immunohistochemical/ biochemical screening
tests, preliminary to molecular diagnosis;
2) standardised prenatal and postnatal molecular diagnostic tests
and a prototype assay based on microchip technology;
3) a virtual biological sample databank.
dissemination of knowledge about clinical features, diagnostic
procedures and management of specific disease groups at a
European scale
close alliance of patients organisations and ethics experts with
physicians and scientists.
The achievement of the proposed objectives will greatly contribute to
the implementation of the Community Policy Objective aimed at
combating rare diseases. In fact, bypassing the problems related to the
rarity of inherited skin diseases, the clinical and research network will
provide a rapid translation of emerging gene discovery and gene

50
RARE DISEASES
Coordinator Centre National de la Recherche Scientifique, Laboratory

Zambruno, Giovanna of Genetic Instability and Cancer UPR 2169-CNRS
Institut Gustave Roussy,
Provincia Italiana della Congregazione dei Figli
Villejuif, France
dellImmacolata Concezione-I.D.I-I.R.C.C.S.
Laboratory of Molecular and Cell Biology Hopital Necker Enfants Malades, Service de
Dermatologie, Paris, France
Via dei Monti di Creta 104
Consortium National de Recherche en Genomique,
00167 Rome, Italy Centre National de Genotypage - Department of
Phone: + 39 0666 464738 Dermatological Diseases,
Fax: + 39 0666 464705 Evry, France
E-mail: g.zambruno@idi.it Assistance Publique - Hpitaux de Paris

Hospices Cantonaux - Centre Hospitalier Universitaire
Project web-site: to be developed.
Vaudois, Service de Dermatologie des Hospices,
Key words: rare genetic diseases, skin, dermatology, Lausanne, Switzerland
diagnosis
Universiteit Gent, Department of Medical Genetics,
Ghent University Hospital, Belgium
Partners Erasmus Medical Center Rotterdam, Medical Genetic
Consiglio Nazionale delle Ricerche, Rome, Italy Cluster - Department of Cell Biology & Genetics,
The Netherlands
Department of Biomedical Sciences, Universit di
Modena e Reggio Emilia, Modena, Italy Academisch Ziekenhuis Gronigen, Department of
Dermatology,The Netherlands
Department of Dermatology, University Hospital,
Freiburg, Germany Asociacion de Epidermolisis Bullosa de Espana, Consejo
Superior de Investigaciones Cientificas, Centro Nacional
Department of Dermatology, University of Munster, de Biotecnologia,
Germany
Departamento de Immunologia y Oncologia,
Centre for Functional Genomics, University of Cologne, Madrid, Spain
University Hospital, Cologne, Germany
Federal Academic Hospital of Feldkirch, Department of
Philipps-Universitaet Marburg, Institut fuer Allgemeine Dermatology, Austria
Humangenetik, Marburg, Germany
Gemeinnutzige Salzburger Landeskliniken
Genetic Skin Disease Group, King's College, London, Betriebsgesellschaft mbH, Dermatology - Laboratories,
United Kingdom Salzburg, Austria
Centre for Cutaneous Research, Queen Mary & Department of Dermato-Venereology Semmelweis
Westfield College, University of London, United Kingdom University, Budapest, Hungary
Genome Damage and Stability Centre, University of Department of Medical Sciences /Dermatology and
Sussex, Brighton, United Kingdom Venereology, University Hospital,
Cancer Sciences and Molecular Pathology, University of Uppsala, Sweden
Glasgow, United Kingdom Uppsala Universitet, Department of Medical Sciences
DebRA Europe, Crowthorne, United Kingdom Dermatology and Veneralogy
Uppsala, Sweden
Our Ladys Hospital for Sick Children, Department of
Paediatric Dermatology, Dublin, Ireland
Institut National de la Sant et de la Recherche Mdicale,
INSERM Units 634, 563 and 217, Acronym: GENESKIN
Nice, France Project number: LSHM-CT-2005-512117
Centre Hospitalier Universitaire de Nice, Service de Instrument: Coordination Action
Dermatologie, Nice, France Duration: 36 months

51
RARE DISEASES EuroWilson
Wilson Disease: Creating a European clinical database and

designing multicentre randomised controlled clinical trials
Summary sulfate (1961), and trientine (1969) were major therapeutic advances.
We now know it to be a disorder of a P-type ATPase situated in the
Wilson Disease is genetic disorder in which deficiency of a copper- trans-golgi,ATP7B, which is a copper transporter. Its deficiency leads
transporting P-type ATPase leads to intracellular retention of to impaired biliary excretion of copper, impaired caeruloplasmin
synthesis, and copper accumulation in the liver, the basal ganglia of
copper in the liver, brain, and kidney. Incidence estimates vary from the brain, and proximal renal tubules.The clinical manifestations are
1/30 000 to 1/100 000. There is controversy as to treatment, diverse. Liver disease is the most frequent presentation in children,
because of a lack of randomised trials comparing copper-chelators and may be of different types and severity. Some present with acute
such as penicillamine or trientine with zinc. In preparation for the liver failure with encephalopathy, requiring urgent transplantation.
Some have a more gradual onset resembling a chronic hepatitis, while
planning of such trials, a European Clinical Database is to be
other may be discovered to have cirrhosis with few symptoms.
established. This will inform us as to the incidence of the disease, Haemolysis is frequently also found. By contrast, older patients tend
its geographical variation, and the frequency of its differing clinical to present with neurological difficulties. Abnormalities of speech,
presentations. coordination and fine motor performance progress to severe tremor,
movement disorder and disability. Other organs are affected to a
variable degree,resulting in joint symptoms,renal disease,and anaemia.
Problem Pre-symptomatic patients are detected through family studies.
It is almost exactly 100 years since Wilson described the neurological Older patients with neurological disease tend to have the common
and liver disorder which bears his name. It was recognised to be H1069Q mutation. However, there is great phenotypic variability
autosomal recessive in inheritance in 1921, and to be associated with amongst patients with the same genotype, and the reasons for this
copper storage in 1945. The discovery of penicillamine (1953), zinc are not known.
The trans-Golgi P-type ATPase, with its 8 transmembrane sections

52
RARE DISEASES
Members of the consortium at a meeting in September 2004
There is a need to determine an optimum treatment regime. A 20 articles described the results of a particular treatment in a series
Cochrane style evaluation of the current literature on Wilson Disease of patients. In only one article, describing 58 patients, both treatment
and treatment yielded over 1000 hits. Over 500 articles were expert options (zinc and D-penicillamine) were evaluated in a non-
opinions in favour of either zinc treatment or the use of copper randomised way. As no strict end points were defined no firm
chelators. No randomised clinical trial could be found, and less than conclusions could be drawn.

53
RARE DISEASES
Aim
The principal aim of this project is to establish a European Clinical The Kayser-Fleischer
Database of newly presenting patients with Wilson Disease. (KF)ring,
copper deposit
Expected results in Descemets
membrane in
We will determine: the eye.
1. the overall incidence of Wilson Disease, and its variation in
different countries.There is an impression of increased incidence
in, for example, Sardinia, but this may be because of better
ascertainment;
Additional benefits
2. the numbers of patients in different clinical categories;
1.The project will bring a profile to a rare disease, provide patient
3. the treatment regimes currently being used and their short-term
and physician information, and stimulate related research.
outcomes;
2.A quality assurance scheme will be established amongst the
4. the genotype of newly presenting patients.
participating molecular diagnostic laboratories.
From this data, the feasibility of a randomised trial will be assessed.
3.The discussions between clinicians about database items are yielding
Phenotypic heterogeneity implies that this will either be a stratified
a valuable consensus about physical sign assessment in Wilson
trial, or a series of trials of homogeneous subsets.
disease, and potentially other disorders.
4. Continuation of the database will provide a long-term research
resource.
5.The data collection system will be useful for other multicentre
studies.

54
RARE DISEASES
Coordinator Dr Loudianos, Georgios

Prof.Tanner, Stuart Dipartimento di Scienze Biomediche e Biotecnologie
Academic Unit of Child Health Cagliari, Italy
University of Sheffield Dr Schmidt, Hartmut
Childrens Hospital Western Bank Med Klinik m.S. Gastroenterologie, Hepatologie, Charite
S10 2TH Sheffield, United Kingdom Universitatsmedizin Berlin
Phone: +44 114 271 7303 Berlin, Germany
Fax: +44 114 275 5364 Dr Melter, Michael
E-mail: m.s.tanner@sheffield.ac.uk Pediatric Gastroenterology, Hepatology and Liver
Transplanatation
Project web-site: www.eurowilson.com
Hannover Medical School
Key words: copper, liver, cirrhosis, movement disorder,
database, randomised trial Hanover, Germany
Dr Houwen, Roderick
Partners Department of Pediatric Gastroentrology
Utrecht,The Netherlands
Prof. Czlonkowska,Anna
Prof. Cohen, Olivier
2nd Department of Neurology
HC Forum, Equipe Genome
Institute of Psychiatry & Neurology
Laboratoire TIMC
Warsaw, Poland
Medical School of Grenoble
Dr Socha, Piotr
La Tronche, France
Dept. of Gastroentology, Hepatology
Mrs Parker, Samantha
The Childrens Memorial Health Institute
Medical and Marketing Department
Centrum Zdrowia Dziecka,
Orphan Europe Sarl
Warsaw, Poland
Paris-La Defense, France
Dr Szonyi, Laszlo
Prof. Sarles, Jacques
1st Department of Paediatrics,
Service de Pediatrie Multidisciplinarire
Semmelweis University
Hopital denfants de la Timone
Budapest, Hungary
Marseille, France
Prof Ferenci, Peter
Dr Dhawan,Anil
Dept. Of Internal Medicine
Division of Hepatology and Transplantation
Medizinische Universitat Wien
Institute of Liver Studies
AKH Wien,Vienna,Austria
Kings College London
Prof. Deutsch, Johann
Medizinishe Universitat Graz
Univ Klinik fur Kinder and Jugendheilkunde
Graz,Austria
Prof.Vegnente,Angela Acronym: EuroWilson
Department of Paediatrics, University "Federico II" EC contribution: 799 645
Naples Instrument: Coordination Action
Duration: 48 months
Naples, Italy Starting date: 01/06/04

55
RARE DISEASES PWS
Prader-Willi Syndrome: A model linking gene expression,

obesity and mental health
Summary The mouse 7C chromosomal region has conserved synteny with the
human 15q11-q13 region. Four potential mouse models with a global
Prader-Willi syndrome is a rare neurodevelopmental disorder with deficiency of paternal gene expression in the 7C chromosomal region,
and therefore potential models for PWS, have been described. The
a characteristic physical and behavioural phenotype that results
observed phenotype is consistent with the feeding difficulties and
from the absence of expression of as yet unidentified maternally- failure to thrive that is characteristic of PWS infants.Thus, complex
imprinted/ paternally-expressed gene(s) at 15q11-13. Seven mouse models provide the means for investigating protein interactions
and signalling pathways linking gene expression to observed
maternally-imprinted genes have been located in the PWS critical
behaviours.
chromosomal region and in the mouse homologues. HBII-52 and
The power of clinical studies of PWS at national levels are limited
HBII-85 in humans, Magel 2, and Necdin are four candidates that
because of the relative rarity of the syndrome. Clinical studies that
will be the focus for developing mouse models in order that include sufficient numbers of people with PWS of different genetic
genotype/phenotype relationships and signalling pathways can be sub-types of both genders across all ages are required to determine
influences on developmental outcomes.
studied. Hypothalamic tissue obtained at post-mortem from people
with PWS will also be used to investigate hypothalamic pathways
known to be important in the control of eating behaviour.The basis
Aim
for a European-wide clinical study of developmental outcomes in 1.To establish specific mouse models of PWS in order to investigate
genotype/phenotype relationships and signalling pathways;
PWS will be established through the development of a clinical
database and its evaluation in specific EU countries. 2. to investigate hypothalamic feeding pathways using post-mortem
tissue from people with PWS;
Problem 3.to establish the basis for a European-wide clinical study investigating
influences on developmental outcomes for people with PWS.
Prader-Willi syndrome is a complex neurodevelopmental disorder
resulting from absent expression of maternally
imprinted/paternally-expressed, but as yet unidentified, gene(s) at Expected results
the locus 15q11-13.The two most common genetic sub-types are
1.The development of a complex mouse model and four specific
chromosomal deletions at 15q11-13 involving chromosome 15 of
knockout mouse models of PWS.
paternal origin and chromosome 15 uniparental maternal disomies.
Two other rare genetic abnormalities are also described.The PWS 2. Full investigation of genotype/phenotype relationships in the
phenotype in infancy is characterised by extreme hypotonia, failure specific mouse models and of the biological functions of the genes
to thrive, hypogonadism, and the need for augmented feeding. From and the associated protein interaction networks and signalling
approximately two years of age, excessive eating becomes apparent, pathways.
remaining throughout life and if left unchecked, leads to severe 3. Investigation of specific hypothalamic feeding pathways in human
obesity and early death. Other diagnostic characteristics include hypothalamic tissue obtained at post-mortem from people with
developmental delay, mild intellectual disabilities, short stature, PWS.
small hands and feet, and delayed sexual development, together with
a propensity to other maladaptive behaviours. This over-eating 4.The establishment of a clinical database compatible with ethical and
behaviour is due to an abnormal satiety response to food intake. clinical practice throughout the EU for the collection of clinical and
In adult life those with PWS due to chromosome 15 maternal research data on people of all ages with PWS.
disomy invariably develop severe affective psychotic illness. Studies 5.The assessment of the database in different European settings.
on post-mortem-obtained hypothalamic tissue have shown a
reduction in oxytocin expressing neurones of the hypothalamus. 6.The integration of data from mouse, human hypothalamic
investigations and existing clinical studies in PWS to inform obesity
So far the function of only two of the hypothalamic peptides
and behavioural research more generally.
important in the regulation of appetite have been investigated and
in these two cases no abnormalities have been found (NPY and
agouti-related peptide).

56
RARE DISEASES
Potential applications Coordinator

For people with PWS and their families it is this extreme propensity
Prof. Holland,Tony
to over-eating and other associated behavioural and psychiatric
problems that has the most significant detrimental effect on their Section of Developmental Psychiatry
quality of life and on life expectancy. Understanding the mechanisms
Department of Psychiatry
in PWS that link genotype to phenotype has the potential to result
in new treatments and will provide models for obesity and University of Cambridge
psychiatric research more generally.The main focus of this project 18b Trumpington Road
is on basic science research but results from subsequent clinical
studies on developmental outcomes will make possible the Cambridge, CB2 2AH, United Kingdom
integration of basic science and clinical data leading to the Phone: + 44 1223 746112
development of more sophisticated models linking the abnormal
expression of imprinted gene(s) to developmental processes and Fax: + 44 1223 746122
specific behavioural and physical outcomes. E-mail: ajh1008@cam.ac.uk
Project web-site: to be developped
Key words: Prader-Willi Syndrome, genomic imprinting,
hypothalamus, obesity
Partners
CNRS/Institut de Biologie du Developpement de
Marseille-Luminy/UMR 6256, Marseille, France
Katholieke Universiteit Leuven, Leuven, Belgium
Section of Biological Developmental Psychology,
University of Maastricht,The Netherlands
Institut fur Humangenetik, Universitat Duisburg-Essen,
Essen, Germany
Netherlands Institute for Brain Research,Amsterdam,
The Netherlands
Department of Womens and Child Health, Karolinska
Institute, Stockholm, Sweden
Department for Functional Genomics, University of
Innsbruck,Austria
Weizmann Institute of Science, Rehovot, Israel
HC Forum, Grenoble, France
Centre Europen de la Recherche en Biologie et en
Mdecine
Acronym: PWS
Duration: 36 months

57
RARE DISEASES EUGINDAT
European genomics initiative on disorders of plasma

membrane amino acid transporters
Summary (IG) and unlabeled aminoacidurias. The proposal aims to study
new candidate genes for cystinuria, DA, HDis and IG.
The project EUGINDAT is an integrated approach that links genetics, 2. to gain a thorough knowledge of the molecular structure of re-
biochemistry, physiology, genomics, proteomics, structural biology, drug levant transporters using 2D crystals of prokaryotic, and event-
development and clinical studies in an attempt to improve understanding ually eukaryotic homologues and 3D crystals of water-soluble
extracellular domains.
and treatment of Primary Inherited Aminoacidurias (PIA). PIA are rare
3. to complete a functional genomic study of relevant transporters
diseases involving defects in renal reabsorption of amino acids that also
underlying PIA and renal reabsorption of amino acids at three levels:
affect other organs.The project applies three main technological avenues i) identification of transporters with a role in the transepithelial
to the study of PIA: I) clinical and genetic characterisation of PIA; II) transport of amino acids in the proximal tubule OK cell model, ii)
functional genomics of renal reabsorption of amino acids; III) structural generation of KO mice,and iii) identification of polymorphisms (SNPs)
in renal transporters that show association with renal reabsorption
biology of PIA-associated amino acid transporters.Moreover,the present of amino acids in genetically isolated human populations.
developments in the clinics and the molecular bases of two of these
4. to identify genes and/or loci that affect cystinuria lithiasis, and may
diseases (Cystinuria and Lysinuric protein intolerance [LPI]) allows the eventually explain gender-related and individual variability in stone-
application of this knowledge to unravel the pathophysiological forming activity in patients with cystinuria.
mechanisms of these diseases and to test new therapeutic strategies. 5. to develop new therapeutic strategies for cystinuria lithiasis.
6. to identify the mechanisms contributing to the pathology of LPI
Problem which explain the hepatic phenotype (hyperammonemia) and the
immune system-compromising symptoms.
PIA are rare disorders of amino acid transporters expressed in the
plasma membrane of renal epithelial cells that impair tubular and 7. to test new therapeutic approaches for the life-threatening
intestinal absorption of amino acids,and that may also affect other organs complications of LPI.
and produce severe clinical consequences. These are rare or orphan
diseases. The orchestrated way in which the various amino acid and
peptide transporters in renal apical and basolateral membranes allow
efficient renal reabsorption of filtered amino acids and provide amino The integrated knowledge to be acquired on PIA within EUGINDAT
acids for the needs of the cells is far from being completely understood. will result in: a) deep clinical and genetic description of PIA, including
very rare forms of these diseases (PIA-DATABASE); b) generation of a
new picture of the physiology and pathophysiology of the cellular
Aim handling of amino acids in the mammalian kidney. Moreover, with the
The EUGINDAT project has two main goals: the first is, to improve capability of crossing animals with defects in individual genes to obtain
our understanding of the genetic, molecular, cellular and physiological multiple knock-out lines a unique European competence area on renal
basis of PIA. amino acid transport processes is created. c) EUGINDAT also takes its
The key goal of the basic science part of EUGINDAT is the most
comprehensive understanding of the inherited aminoacidurias by
analysis of the patho-physiological processes down to individual
proteins and genes followed by a systematic reintegration of the
knowledge gathered to the most complex level of the organisms.
The second goal is to explore new strategies for the diagnosis and
therapy of these diseases, including improved patient care based on
the knowledge generated in the project.
Expected results
1. to complete a clinical and molecular-genetic description of PIA
with the generation of a European PIA-DATABASE including:
Cystinuria, Lysinuric Protein Intolerance (LPI), Dicarboxylic Chimeras used to generate the LAT-2 knock-out mouse model
Aminoaciduria (DA), Hartnup Disorder (HDis), Iminoglycinuria

58
RARE DISEASES
world-recognised expert knowledge and its technological capabilities to

Dr Fotiadis, Dimitrios
work on the carrier protein structures,which represents an added value
Maurice E. Mller Institute at the Biozentrum,
as this area has traditionally been solely in the hands of biochemists,
University of Basel
physicist or chemists. The 3D structure of amino acid and peptide
transporters related to PIA and nutrition will provide the basis for the Basel, Switzerland
understanding of the malfunctions of the proteins based on sequence- Dr. Kanner, Baruch
dependent conformational alterations in substrate binding and transport The Hebrew University of Jerusalem
capability and protein stability. d) Finally, information gained on PIA Jerusalem, Israel
diseases is being transferred into development of new drug and Huoponen, Kirsi
therapeutic approaches for Cystinuria and Lysinuric protein intolerance. University of Turku, Department of Medical Genetics
Turku, Finland
Dr. Simell, Olli
University of Turku, Department of Pediatrics
Coordinator Turku, Finland
Dr Palacn, Manuel
Dr Wagner, Carsten
Universitat de Barcelona
Institute of Physiology, University of Zurich
Facultat de Biologia
Zurich, Switzerland
Department de Bioqumica y Biologia Molecular
Prof.Verrey, Franois
Avgda. Diagonal, 645. Edifici Nou.
Institute of Physiology, University of Zurich
Planta 1
Zurich, Switzerland
08028 Barcelona, Spain
Prof. Borsani, Giuseppe
Phone: +34 93 403 4617- Fax: +34 93 402 1559 University of Brescia, School of Medicine
Email: mpalacin@porthos.bio.ub.es Department of Biomedical Sciences and Biotechnologies
Project web-site: http://www.ub.edu/eugindat Brescia, Italy
Key words: amino acids, transporters, primary inherited Prof. Lang, Florian
aminoacidurias, Cystinuria, Lysinuric protein
Department for Physiology, University of Tubingen
intolerance, Dicarboxylic aminoaciduria,
Hartnup disorder, Iminoglycinuria, genomics, Tubingen, Germany
structural studies, knock-out models. Dr Della Strogalo, Luca
Head Dpt. Of Nephrology and Urology
Partners Childrens Hospital and Research Institute Bambino Ges
Dr Orozco, Modesto Rome, Italy
Universitat de Barcelona Dr Bisceglia, Luigi
Facultat de Qumica IRCCS Casa Sollievo della Sofferenza, Servizio di Genetica
Dept Bioqumica y Biologia Molecular (Biologia) Medica
Barcelona, Spain San Giovanni Rotondo (FG), Italy
Prof. Daniel, Hannelore Dr Pras, Elon
TU Mnchen Institute of Human Genetics
Wissenschaftszentrum Weihenstephan Sheba Medical Center, Israel
Institut fr Ernhrungsphysiologie Dr Rubio, Guillermo
Freising-Weihenstephan, Germany Laboratorios Rubi, S.A
Dr Nunes,Virginia Castellbisbal, Spain
Centro de Gentica Mdica y Molecular Dr Grosse, Johannes
Institut de Recerca Oncologica (IRO) Ingenium Pharmaceuticals AG
Hospital Duran i Reynals Director Bussines Development, Program Partnering
Spain Martinsried, Germany
Dr Gasparini, Paolo
Fondazione Telethon
Acronym: EUGINDAT
Rome. Italy Project number: LSHM-CT-2003-502852
Prof. Sebastio, Gianfranco EC contribution: 3 050 000
Professore Associato di Pediatria, Universit Federico II Instrument: Specific Targeted Research Project
Duration: 36 months
Naples, Italy Starting date: 01/03/2004

59
RARE DISEASES EURAPS
Autoimmune polyendocrine syndrome type I a rare

disorder of childhood as a model for autoimmunity
Summary an early age with both endocrine and non-endocrine tissues affected,
and in addition, mucocutaneous candidiasis that is often a hallmark of
Autoimmune polyendocrine syndrome type I (APS I; OMIM 240300), the disease. APS I is more common in certain areas, such as Finland
(prevalence 1/25 000) and Sardinia.A number of autoantigens have been
a rare genetic disorder of childhood with autoimmune reactions against
identified in APS I.These discoveries have provided diagnostic tools and
a range of different tissues, has been shown to be an invaluable tool in predictive markers for the appearance of various clinical components
understanding autoimmune reactions. APS I is characterised by of the disease. Furthermore, some of the autoantigens identified in APS
I have later been shown to be of importance in more common
autoantibodies against several defined autoantigens often identical to
autoimmune disorders. The AIRE gene product is most prominently
those found in common autoimmune disorders such as type 1 diabetes expressed in the medullary epithelial cells of the thymus. Thymic
mellitus.The cellular and molecular mechanisms leading to this complex medullary epithelial cells are involved in the negative selection of
syndrome remain, however, incompletely understood. Studies on lymphocytes during the lymphocyte maturation process in the thymus.
An analysis of the cellular and functional consequences of different
recently generated animal models for the disease, as well as genomic- missense mutations of the AIRE gene product has allowed a detailed
wide approaches to identify immune-modulating genes, will provide mapping of the various functional domains of the protein. Several lines
novel information of importance not only to the patients affected with of Aire -/- mice have been generated providing an excellent animal model
for the disease.Despite these recent advances,the physiological function
this rare disorder, but will also increase our understanding of the of AIRE or the mechanisms responsible for autoimmunity when AIRE is
pathogenesis of autoimmune diseases in general. defective are not yet fully understood. The reason for the
mucocutaneous candidiasis infection occurring in almost all patients
remains completely obscure.
Problem
APS I (OMIM 240300), also known as APECED (autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy) is an autosomal
Aim
recessive disorder caused by mutations in the AIRE gene on The first objective is to use this disorder as a model to understand
chromosome 21. Patients develop the first symptoms of the disease at the immunological mechanisms at a molecular level that predispose
to autoimmunity and to the propensity to develop fungal infections.
The second objective is to provide better care of patients with APS
I by developing new diagnostic tests, revising the diagnostic criteria,
Embryonic thymus and improving the understanding of the clinical course and the long-
day 13 of gestation. term complications.
Cortical epithelial
cells are stained in
green for Keratin 8,
Expected results
medullary epithelial 1. Establishment of a pan-European database and biobank for APS I
cells to be are patients.
stained in pink for 2. Increased awareness of the disease among physicians and dis-
cytokeratin 5 and semination of knowledge about recommended follow-up procedures
MTS10 cell antigen and diagnostic and therapeutic options.
3. Define the function of the AIRE gene product in thymic T cell
development and in the establishment of tolerance.
Staining of Paneth cells 4. Identification T cell and B cell epitopes of defined autoantigens.
(producing defensins and 5. Discovery of genes that modify the intensity and/or course of APS I.
enzymes important to 6.A collection of expression profile data from cells and tissues with a
the host defence against normal or defective AIRE to identify targets regulated by AIRE.
bacterial, fungal and viral
7. Elucidation of the mechanisms underlying the propensity to develop
infections) in the small mucocutaneous candidiasis.
intestine using a serum
from a patient with
autoimmune polyen-
docrine syndrome type 1.

60
RARE DISEASES
Identification of modulating genes for the disease, of factors in the up-
stream regulation of AIRE gene expression and of proteins down-stream Lund, Sweden
regulated by the AIRE gene product,will all undoubtedly help in identifying Prof. Husebye, Eystein S.
important drug targets for the modulation of various immune reactions. University of Bergen
Also,the discovery of novel autoantigens will improve the clinical follow- Endocrinology unit, Institute of Medicine
up of APS I patients and may be of value in the diagnosis of other Bergen, Norway
autoimmune disorders not associated with APS I.Moreover,clarification Prof. Manns, Michael P.
of the mechanisms underlying the propensity to develop mucocutaneous Medizinische Hochschule Hannover
candidiasis can lead to novel therapeutic possibilities. Department of Gastroenterology, Hepatology and
Endocrinology
Hanover, Germany
Prof. Palmer, Ed
Coordinator University Hospital Basel
Prof. Kmpe, Olle Basel, Switzerland
Uppsala University Prof. Peltonen, Leena
Department of Medical Sciences National Public Health Institute
University Hospital Department of Molecular Medicine
75185 Uppsala, Sweden Helsinki, Finland
Phone: + 46 186 112 978 Prof. Peterson, Prt
Fax: + 46 185 25795 University of Tartu, Institute of General and Molecular
E-mail: olle.kampe@medsci.uu.se Pathology
Project web-site: Tartu, Estonia
http://www.molecularmedicine.se/EURAPS Prof. Romani, Luiginia
Key words: rare disorders, autoimmunity, University of Perugia, Department of Experimental
polyendocrinopathies; thymus, disease mod- Medicine and Biochemical Sciences
els, Perugia, Italy
Partners Prof. Samaranayake, Lakshamn P.
Prof. Betterle, Corrado University of Hong Kong
University of Padua Department of Oral Microbiology, Faculty of Dentistry
Department of Medical and Surgical Sciences, Hong Kong, China
Endocrine Unit Prof.Weetman,Anthony P.
Padua, Italy University of Sheffield, Division of Clinical Sciences
Prof. Cahill, Dolores Clinical Sciences Centre, Northern General Hospital
Royal College of Surgeons in Ireland Sheffield, United Kingdom
Dublin, Ireland Prof. De Virgiliis, Stefano
Prof. Cerundolo,Vincenzo University of Cagliari, Dipartimento di Scienze
University of Oxford, Department of Medicine,Tumour Biomediche e Biotecnologie
Immunology Unit Laboratorio di immunologia e genetica molecolare,
The Weatherall Institute of Molecular Medicine Clinica Pediatrica
Cagliari, Italy
Oxford, United Kingdom
Prof. Scott, Hamish S.
Prof. Goodnow, Christopher C.
Walter and Eliza Hall Institute
The Australian National University
Genetics and Bioinformatics Division
Medical Genome Centre, John Curtin School of Medical
Research, Canberra,Australia Parkville, Australia
Prof. Hollnder, Georges
University of Basel, Pediatric Immunology
Department of Clinical-Biological Sciences Acronym: EURAPS
Basel, Switzerland Project number: LSHM-CT-2005-005223
Prof. Holmdahl, Rikard EC contribution: 3 000 000
Lund University, Department of Cell and Molecular Duration: 36 months
Biology Starting date: 01/05/2005

61
RARE DISEASES AUTOROME
From immune responses in rare autoimmune diseases

to novel therapeutic intervention strategies -
a personalised medicine approach
Summary by profiling autoantigens and autoantibodies and determine the
major autoreactive epitopes
Rare autoimmune diseases are chronic inflammatory diseases affecting by addressing mechanisms that determine the initiation,progression
a large number of the European population. Chronic inflammation and chronicity of the humoral immune response on the cellular level
leading to destruction of target organs results in disability and enormous (T-cells,APC cells, B-cells, epithelial cells)
human suffering and to large socio-economic costs. Therefore, by characterising cellular differentiation, maturation and migration
processes with a strong focus on B cell development, making use of
understanding its pathogenesis constitutes an R&D area of strategic
animal models
importance, both, scientifically and also socio-economically. This
by developing therapeutic approaches to eliminate autoantibody-
proposal integrates leading groups with state-of-the-art resources and producing cells.
projects from academia and SMEs by creating a critical mass sufficient
Novel human and murine autoantigens will be characterised and
to promote R&D interactions between basic and applied science.The epitope and paratope mapping will be performed. Peptide and
work will lead to a better understanding of mechanisms that contribute autoantigen filters/chips will be validated in concert with clinical
to rare autoimmune diseases and provide us with leads for improved partners leading to diagnostic kits. Anti-idiotypic antibodies will be
analysed from intravenous immunogloblulin fractions (IVIG).Idiotypic
diagnostics and therapeutics. peptides and therapeutic antibodies are generated and validated in
functional assays as well as in animal models. Cell types and
Objectives differentiation steps of the cellular immune system are studied in
different mouse models.This analysis is complemented by FACS sorted
Rare autoimmune diseases e.g. various subtypes of systemic vasculitis, cellular blood components derived from diseased patients to be
are associated with substantial morbidity and even accelerated mortality studied in depth on the transcriptome and proteome level in order
in affected persons (children and elderly). In many cases these diseases to functionally analyse molecular parameters found in rare
are systemic,inflammatory,progressive,chronic and destructive diseases autoimmune diseases under study.
affecting numerous organs and tissue types.These diseases are associated
with pain, and various organ manifestations (entitled
syndromes) leading to organ failures and final death. One
of the hallmarks of rare systemic autoimmune diseases is
the formation of autoantibodies driving the pathology of
the disease.These autoantibodies are directed e.g. against
negatively charged phospholipids as in the anti phospholipid
syndrome (APS), against components of the nucleus such
as DNA, RNA, histones, nuclear proteins and protein-
nucleic acid complexes as in SLE and against nuclear
components like centromer antigens or topoisomerase I
as in systemic scleroderma (SSC).As of yet it is not clear
how the different autoantibodies contribute to the organ
specific pathologies of the various diseases. Neither clear-
cut diagnostics and prognostics nor specific therapeutics
ultimately leading to a cure of the disease are available.
Work packages
AUTOROME is dedicated to improve the current state-
of-the-art methodology in the understanding of
aetiology, pathophysiology, progress and therapy of rare
autoimmune diseases by conducting the following work
packages:
Project overview

62
RARE DISEASES
Expected results Potential applications

Comprehensive technology platforms (including protein chips, mass Diagnostic tools assessing the relevance and distribution of pathogenic
spectrometry, phage libraries, immunoscoping) will be employed to antibodies in individual patients are one essential milestone in
identify autoantibodies, autoantigens and epitopes contributing to generating and selecting appropriate therapeutic interventions
disease initiation, progression and chronicity. The rationale of novel strategies.The generation and administration of anti-idiotypic peptides
therapeutic strategies depending on the generation of anti-idiotypic interfering with pathogenic antigen-antibody interactions is one way
peptides and therapeutic antibodies as well as siRNA constructs will to help patient suffering from severe autoantibody-mediated
be evaluated. In a personalised manner pathogenic B cells and plasma autoimmunities.The analysis of autoimmune diseases might become
cells will be targeted related to the disease parameters found in a leading force on the way to more personalised therapeutic strategies
individual patients determined by spectratyping and mass and prevention. Reducing the incidence, prevalence and severity of
spectrometric autoantibody characterisation.Expected achievements autoimmune diseases consequently relieves the economic and social
and deliverables of this proposal are likely to also help to elucidate impact on health-care costs for any society.
molecular mechanisms in immune processes and autoimmune diseases
in general and will,therefore,be of broad scientific and socio-economic
value. Specific expected results are:
Coordinator
identification of novel autoantigens and immuno-dominant epitopes
in rare autoimmune diseases Prof.Thiesen, Hans-Jrgen
identification of immune cell subsets associated with rare Institute of Immunology

autoimmune diseases University of Rostock
description of autoantibody profiles specific for individual patients, Schillingallee 70
specific diseases and in animal models
18055 Rostock, Germany
identification of novel target genes in rare autoimmune diseases
Phone: +49 381 494 5870
elucidation of synthetic autoreactive peptides and siRNAs for the
development of specific modulators of the pathogenic humoral Fax: +49 381 494 5882
immune response Email: hans-juergen.thiesen@med.uni-rostock.de
development of diagnostic tools to assess disease severity and to Project web-site: http://www.autorome.de
predict disease onset
Key words: anti-idiotypic; anti-phospholipid syndrome
detailed characterisation of human B cell development and selection (APS); autoimmune lymphoproliferative
elucidation of autoimmune pathways and therapeutic approaches syndrome (ALPS); autoimmunity; autoanti-
using mouse models gen; autoantibody; systemic lupus erythe-
matosus (SLE); systemic scleroderma; sys-
improved understanding of the immunopathology of autoimmune temic vasculitis
diseases
Finally, prognostic markers and diagnostic tools should lead to Partners
individualised therapeutic approaches using idiotypic peptides as well
as therapeutic antibodies and siRNA. Synthetic peptides will be 2 France
generated and applied for the following aims: 1) to develop an ELISA 3 Denmark
kit for detection of autoAbs specific for thrombosis-associated
pathogenic epitopes in order to predict thrombotic risk or recurrent 3 Switzerland
fetal loss in patients having these specific autoAbs; 2) to neutralize 1 Ireland
the biological activity of the studied autoAbs, in vivo and in vitro; 3)
to induce specific B cells apoptosis of the pathogenic autoAbs 1 Israel
secreting cells. 1 The Netherlands
Acronym: AUTOROME
Duration: 36 months

63
RARE DISEASES Orphanplatform
A European platform of integrated information services for

the coordination of rare disease research in Europe,
with various stakeholders from research, SMEs and patient
organisations and the coordination of early clinical trials
Summary Patients suffering from such conditions should benefit from the same
quality of treatment as other patients. Treatment of the very small
The project aims at developing information tools to address in a number of patients affected by a specific rare disease results in
fragmentation of research efforts and limited potential for
comprehensive and integrated approach the set of factors that
commercial development of medicinal products. Therefore it is
currently affects research on rare diseases and its coordination.The essential to act at a European level.
specific objectives are: (1) to develop an information service, freely The Fifth Framework Programmes for Research and Technological
accessible on the Internet, dedicated to research activities in the field Development has supported research on rare diseases, to promote
of rare diseases and orphan medicinal products, including a database the establishment of cross-national cooperation.The EU gives priority
to rare diseases within the new EU public health framework.The EU
of research projects, funded at MS level and at the EU level, and a
Regulation on Orphan Medicinal Products (OMP) was adopted in
database of collections and research networks;(2) to develop services order to stimulate prevention and development of new diagnostic
aiming at speeding up the enrolment of patients in clinical research; tools, and therapies for rare diseases. It is highly effective.
(3) to develop a database of research projects with development Several Member States have taken initiatives to support research in
potential, to help scientists and industry establish the necessary the field of rare diseases. France, Germany, Ireland and Spain have set
up specific programmes to support networking activities. France,
partnerships; (4) to organise a workshop with all stakeholders to Germany,Spain,Italy and the Netherlands have established committees
discuss identified bottlenecks and find solutions.This project is based to review research activities and advise on research issues at the
on input from the following (1) an EU-funded information service on governmental level.Several charity organisations are strongly involved
in the field, especially the French and Italian Telethons.
rare diseases: Orphanet (www.orpha.net); (2) a European platform of
patients organisation, science and industry (EPPOSI) which actively
supports partnering activities; (3) an umbrella organisation of patient
support groups (Eurordis) involved in supporting research and
regulatory activities.The project aims at establishing the platform of
services in 11 European countries in the pilot phase in order to
propose an extension to the 25 European countries within two years.
Ultimately, the goal is to convert scientific developments into
diagnostic tools and therapies as quickly as possible.
Problem
Over 20 million Europeans are affected with rare diseases.Almost all
these rare diseases are life-threatening or chronically debilitating
disorders and most of them are genetic.To date, 5000 to 8000 phe-
notypes have been described among which 2000 are already assigned
to one or several genes. Rare diseases are of the utmost importance
in terms of both public health and scientific challenge as they are due
to the failure of unique physiological pathways.Moreover,rare diseases
represent an experimental model of normal cellular and tissular
function of cells and contribute to a better understanding of more
common diseases as well as paediatric diseases.
The Orphanplatform website

64
RARE DISEASES
Aim 3) Availability of OrphanXchange, a marketplace of research projects

of potential interest for biotech and pharma industry.This service
The project aims to develop information tools in order to address in is expected to contribute significantly to the transfer to the market
a comprehensive and integrated approach the set of factors that of innovative therapeutics, devices and new diagnostic tools.
currently affects research on rare diseases and their validation at
4) Organisation of a partnering workshop which will bring together
European level. Ultimately, the goal is to convert scientific
patient representatives, scientists, clinicians, industry
developments into therapies as quickly as possible and to ensure
representatives and capital providers. Its objectives are to find
timely access to innovative practices, tools and medicines.
means of facilitating mutual understanding between the parties
involved; to identify roadblocks in the development of therapies
for rare conditions and to examine possible means around these
roadblocks; to support partnerships; to disseminate expert
knowledge to all participants, researchers, patient organisations,
industry and regulators.
The project also addresses the needs of diseases specific research
networks.Through bridging the upstream needs for data availability
with the downstream issues faced by clinical researchers, the project
aims at building synergies with, and acting as a facilitator for other
important research and development projects in the fields of rare
disorders, genomics and post-genomics, gene and cell therapies.
The project addresses the needs of EMEA and industry.The project
is of course directly relevant to the activities of the Committee for
Orphan Medicinal Products and of the Committee for Medicinal
Products for Human Use, including its Scientific Review Group to
provide protocol assistance and its safety, efficacy and quality working
parties. The project is also expected to have direct benefits for
European industry and particularly for small and medium enterprises
(SMEs), which account for 80% of OMP applications submitted to
EMEA. The platform of services at the centre of the project will
provide these industry partners with cost-effective services and
solutions that are not yet available. The platform will also steer
innovation capacity for new therapies and will reduce the current
competitiveness gap of EU industry versus US.
The project will benefit paediatric drugs and cancer treatments
Orphanet, the European database on rare diseases and orphan drugs development.This represents another major public health objective
for the EU on which the European Commission envisages specific
regulatory and research initiatives. 80% of rare diseases appear at an
early age and are directly responsible for 25% of the mortality in
Expected results childhood.
1) Availability of a European Internet-based information system able The project is an archetype of the need for action at European level.
to provide the rare disease research community with accurate, The specificity of the small number of patients, scarce professional
reliable and comprehensive European data on existing research competences and fragmented resources are defining the relevance of
projects and networks, registries of cases, directories of patients, this structuring project at EU level.
cohorts of patients, networks of banks and available biological
resources. This information is expected to facilitate exchanges
between various stakeholders and to stimulate cooperation
between research groups.
2) Availability of an on-line service to speed up the enrolment of
patients in clinical research projects. This service is expected to
facilitate and to accelerate enrolment of patients in clinical research
studies, leading to money savings and to a higher chance to finalise
the projects.

65
RARE DISEASES
Coordinator Prof. Kriinen, Helena

Dr Aym, Sgolne University Turku
INSERM Department of Medical Genetics
SC11 Turku, Finland
Hpital Broussais, 102 rue Didot Dr Lassale, Catherine
75014 Paris, France Les Entreprises du Mdicament
Phone: +33 1 56 53 81 37 Paris, France
Fax: +33 1 56 53 81 38 Dr Oosterwijk, Cor
E-mail: ayme@orpha.net Vereniging Samenwerkende Ouder- en
Project web-site: http://www.orphanplatform.org, Patientenorganisaties
http://www.orphanxchange.org, http://www.orpha.net. Soestdijk,The Netherlands
Key words: rare diseases, genetic diseases, orphan Mr. Poortman,Ysbrand
drugs, information systems, database, technology transfer, EPPOSI
clinical research, clinical trials
Soestdijk,The Netherlands
Ms Jrgen Reden
Partners EBE EFPIA
Dr Buckley, Brendan Brussels, Belgium
European Centre for Clinical Trials in Rare Diseases Dr Reis Lima, Margarida
Cork Airport, Ireland Instituo de Gentica Mdica Jacinto Magalhes
Prof. Dallapiccola, Bruno Porto, Portugal
IRCCS Prof. Schmidtke, Joerg
Rome, Italy Medizinisch Hochschule Hannover
Dr Del Campo, Miguel Institut fr Humangenetik
Universitat Pompeu Fabra Hanover, Germany
Department Cieucies Experimentals Dr Squiban, Patrick
Barcelona, Spain Europabio
Prof. Donnai, Dian Strasbourg, France
The Victoria University of Manchester Dr.Voigtlander,Till
Academic Unit of Medical Genetics Medical University of Vienna
Manchester, United Kingdom Institute of Neurology
Prof. Fryns, Jean-Pierre Vienna, Austria
Katholieke Universiteit Leuven
Center of Human Genetics
Leuven, Belgium Acronym: Orphanplatform
Mrs Greene, Lesley EC contribution: 400 000
EURORDIS Instrument: Specific Support Action
Duration: 24 months
Crewe, United Kingdom Starting date: 01/04/2004
Prof. Hennekam, Raoul
Universiteit van Amsterdam
Dept of Pediatrics and Clinical Genetics
Amsterdam,The Netherlands

66
Anti-Microbial
Drug Resistance
EUR-INTAFAR 68
ActinoGEN 70
VIRGIL 73
PNEUMOPEP 75
AMIS 77
PREVIS 79
COBRA 82
micro-MATRIX 85
AMDR EUR-INTAFAR
Inhibition of new targets for fighting

antibiotic resistance
Summary
Peptidoglycan biosynthesis and bacterial cell morphogenesis are related
phenomena and are totally specific to bacterial cells without even
remotely equivalent systems in eukaryotic cells. The enzymes and
proteins involved in these processes are thus potential targets for the
design of new antibiotics. Interfering with the activities of the
participating enzymes or with the protein-protein interactions which
take place along these metabolic pathways should result in the
perturbation of the bacterial cell cycle and, hopefully, supply new
weapons in the fight against dangerous pathogenic organisms such as
the methicillin-resistant Staphylococcus aureus (MRSA).
Structure of the Mur D ligase of Escherichia coli

Problem (Bertrand et al., J. Mol. Biol., 289, 579-590, 1990)
Although antibiotics have drastically reduced illness and death from
infectious diseases, bacteria have exhibited a remarkable capacity to
areas which have been relatively neglected in the recent past when
quickly become resistant to one or several classes of antibiotics. For
compared to eukaryotic systems.
example, in the US, until 2000, Streptococcus pneumoniae infections
caused, each year, 100 000 to 135 000 hospitalisations for pneumonia,
6 million cases of otitis media and 60 000 cases of invasive diseases Aim
including 3 300 cases of meningitis. Up to 40% of the infections were
caused by bacteria resistant to at least one and 15% to three or more The aim of this network is to find new potential targets for antibiotics
antibiotics. The percentage of S. pneumoniae strains resistant to and to use the knowledge accumulated on the antibiotic-resistant
penicillin varies from 3.2 in The Netherlands to 53 in France.Values forms of some old targets for the design of more efficient molecules.
as high as 60 and 78% are observed in Hong Kong and Saudi Arabia, To do so, the fundamental aspects of peptidoglycan biosynthesis and
respectively. Resistance to -lactams is often associated to resistance bacterial cell morphogenesis will be investigated. The phenomena
to macrolides. which take place at the level of the cytoplasmic membrane and are
In 1996, two million cases of nosocomial infections were counted still very poorly understood will receive special attention.
annually in US hospitals. Their global cost ranged from $600 for a
urinary infection to $40 000 for a septicemia. Extrapolations made in Expected results
1996 in a French study showed that due to nosocomial infections, the
stays in hospital were three to seven days longer and the expenses 1.The design, synthesis and evaluation of inhibitors or inactivators
per patient were 750 to 1500 higher. These annual extra costs of the penicillin-resistant DD-transpeptidases. In sensitive
represented about 2% of the total hospital expenses. bacteria, these enzymes, often referred to as PBPs (for Penicillin
Binding Proteins) and which catalyse the final step of
Strains isolated from farm animals present even higher levels of
peptidoglycan biosynthesis are the targets of penicillins and
resistance. In a recent study performed in Belgium, 95% of the
related compounds.
Escherichia. coli strains isolated from poultry, 44% of the strains of
bovine origin and 90% strains of porcine origin were resistant to 2.The development of inhibitors of the glycosyltransferase domain
tetracyclines. In all of these cases, resistance to aminoglycosides of class a PBPs.The reaction catalysed by this enzyme immediately
(streptomycin),chloramphenicol and amoxycillin or ampicillin was also precedes the transpeptidation reaction. No clinically useful
widespread. inhibitor of this activity is known.
The increase in antibiotic resistance is thus a global problem, both for 3. Characterisation of the membrane steps involved in the synthesis
nosocomial as well as community-acquired infections.A return to the of the immediate precursor of the transglycosylation reaction
pre-antibiotic era has even been forecasted. Hence the problem of (the lipid II) and of the mechanism responsible for the
resistance can only be solved by a multidisciplinary and international translocation of the disaccharide peptide moiety of lipid II across
approach,which will require a better understanding of the fundamental the membrane and design of inhibitors of these processes.
aspects of bacterial physiology,growth and multiplication mechanisms,

68
AMDR
4.The development of inhibitors targeting the intracellular steps

of soluble precursor synthesis which will rest in part on the Coordinator
differences in the structures of the peptide moieties in several
Gram positive pathogens such as Staphylococcus aureus, Jean-Marie Frre
Streptococcus pneumoniae and Enterococci.Elucidation of the role
Centre for Protein Engineering, Institut de Chimie B6a,
of the Mur synthetases in Chlamidiae, bacteria which lack
University of Lige
detectable peptidoglycan.
4000 Lige, Belgium
5. Understanding the integration of the peptidoglycan manufacturing
machineries in the cell morphogenesis and regulation apparatus. Phone: +32 43 663398
A number of proteins which regulate processes such as cell
Fax: +32 43 663364
elongation and division are known but their exact modes of action
remain to be clarified. Compounds which can interfere with the Project web-site:
protein-protein interactions involved in these machineries are (in creation)
potential antibacterial compounds. http://www.ulg.ac.be/cingprot/intafar.htm
Key words: antibiotics, peptidoglycan, bacterial cell
Potential applications morphogenesis, transpeptidase, transgly-
cosylase, Lipid II, Mur proteins, Fem proteins
New antibiotics are needed to fight the multi-resistant pathogens.
Large pharmaceutical companies have been leaving the field of
antibacterial research for a number of years. Although the potential Partners
antibiotic market remains huge,up to 90% of infections can be treated
Molecular Cytology, Swammerdam Institute for Life
with the presently available compounds. The design of specific
Sciences, University of Amsterdam,The Netherlands
antibacterial agents directed towards specific species or strains is a
sensible strategy from a public health point of view. It is much less UMR 8619 CNRS, Institut de Biochimie, Universit de
interesting commercially. Indeed, a good antibiotic is expected to be Paris-Sud, France
taken by the patient over a short period of 1-2 weeks.In consequence, Department of Biochemistry of Membranes, Utrecht
if public authorities do not take charge of the problem, it will remain University,The Netherlands
unsolved at a large cost for society.
LCM, Institut de Biologie Structurale, Grenoble, France
This project is of prime importance as a springboard to re-activate
the utmost important area of antibiotic drugs. Mikrobielle Genetik, Universitt Tbingen, Germany
Department of Microbiology, University of Kaiserslautern,
A better understanding of the physiology and biochemistry of bacterial
Germany
cell morphogenesis and peptidoglycan biosynthesis will create new
avenues for the design and synthesis of efficient antimicrobials.This L.R.M.A./E0004, Universit Paris VI, France
will make new opportunities available for companies of different sizes Division of Microbiology, School of Biochemistry and
to develop these compounds until they reach the clinical level. Molecular Biology, University of Leeds, United Kingdom
LCM, Institut de Biologie Structurale, Grenoble, France
Centre de Recherches du Cyclotron B30, University of
Lige, Belgium
Oxford Centre for Molecular Sciences and Dyson Perrins
Laboratory, United Kingdom
Laboratoire de Chimie et Biochimie, Universit Ren
Descartes, France
Faculty of Pharmacy, University of Ljubljana, Slovenia
Lek, d.d. Pharmaceutical and Chemical Company,
Ljubljana, Slovenia
ProtNeteomix, Universit de Nantes, France
Acronym: EUR-INTAFAR
Duration: 60 months

69
AMDR ActinoGEN
Integrating genomics-based applications to exploit

actinomycetes as a resource for new antibiotics
Summary drugs is no longer considered to be economically worthwhile.
Unfortunately, the downturn in drug discovery has coincided with a
ActinoGEN is an Integrated Project aimed at developing novel dramatic worldwide increase in the incidence of resistance to all the
antibiotics currently used in medicine.
genomics-based approaches to exploit hitherto overlooked genetic
resources for new antibiotics.Drug discovery will focus on (1) accessing
new antibiotic biosynthetic pathways from diverse actinomycetes that
Aim
have yet to be cultured; (2) activating cryptic pathways from well- The aim of this project is to combine new functional genomic
technologies with chemical analysis in an integrated multidisciplinary
characterised actinomycetes;and (3) engineering novel hybrid antibiotics
approach, both to exploit hitherto overlooked genetic resources for
by combinatorial biosynthesis.To greatly accelerate the drug discovery new antibiotics and, secondly, develop generic superhosts to
process, a parallel strategy will be to engineer generic hosts optimised produce these new antibiotics in high yields. ActinoGEN proposes
three parallel objectives to discover and develop new antibiotics
to produce high antibiotic yields.With the complete genome sequence
based on exploiting the genetic resources of actinomycetes, hitherto
of the model actinomycete, Streptomyces coelicolor, and mobilisation of the major source of existing antimicrobials.The first of these is to
a pan-European effort to apply newly developed multidisciplinary post- activate cryptic antibiotic biosynthetic pathways. Recent genome
genomic technologies, a holistic understanding of the physiology and sequencing projects have revealed a genetic potential for
actinomycetes to produce many more antibiotics than previously
regulation of antibiotic biosynthesis will be achievable for the first time. recognised. ActinoGEN will explore how different cryptic pathways
This will,in turn,permit rational intervention to engineer generic hosts can be activated and then determine the structures and activities
for high-yield antibiotic production.This synergy of discovery linked to of the resulting new antimicrobials. The second approach will rely
on the discovery of new antibiotic biosynthetic pathways from
overproduction will place the European biotechnology sector at the
diverse actinomycetes. The number of actinomycete species that
forefront of developing much-needed new antibiotics
to combat multi drug-resistant pathogens.
Problem
Multiple drug-resistant bacteria are a major threat to
human health and a significant burden on already
stretched medical budgets.This threat is predicted to
increase in severity, and remedial actions of reducing
antibiotic use in animal husbandry and limiting current
prescribing activities for non-lethal human disease are
both unlikely to reduce the danger in the short term. Genetic engineering of
Of major concern are antibiotic-resistant nosocomial cosmid clones for het-
infections.The economic and societal costs of these erologous expression of
hospital-acquired infections are enormous: the UK new antibiotics (provid-
National Health Service has estimated an annual cost ed by Bertolt Gust and
of 1.5 billion for extra patient care and that 5000 Lutz Heide).
deaths result each year. In addition, the incidence of
infection by multiple drug-resistant strains of
Mycobacterium tuberculosis,the causative agent of the
tuberculosis, is rapidly increasing, particularly among
the disadvantaged in society. Investment in R&D into
antibiotic discovery by the major pharmaceutical
companies has declined dramatically in the last 15 years
as a perception has taken hold that easily obtained
natural products may have been fully exploited.Hence
conventional screening of natural products for new

70
AMDR
Secreted droplet of antibiotic on the surface of the model actino-

mycete Streptomyces coelicolor: the shape of the droplet is a con-
sequence of hydrophobicity of the colony surface due to surface-active
chaplin proteins (provided by Lubbert Dijkhuizen).
have been isolated to date represents a small fraction of the total

in the environment. ActinoGEN will exploit the untapped genetic
resource of as yet uncultured species to obtain antibiotic
biosynthetic gene clusters that can direct synthesis of new
antimicrobials. A third route to new antimicrobials is by
combinatorial biosynthesis. Biosynthetic genes from both new and
existing pathways will be combined to direct synthesis of new
antibiotics with predicted structures. The design of new hybrid
molecules will be related to improving antimicrobial activity. A fourth
major aim, underpinning the Drug Discovery objectives, is the
engineering of generic superhosts for antibiotic production. A rate-
limiting step to developing a new antibiotic is yield improvement.
Post-genomic analysis permits, for the first time, a concerted and
holistic approach to engineering generic superhosts for use in the
production of high yields of a wide variety of antibiotics. As part of
ActinoGEN, this complementary activity is vital to greatly accelerate
the discovery and development of new drugs.
Expected results Genetic and environmental influences on antibiotic production:

1.The establishment of generic procedures for the activation of (A) actinomycetes such as S. coelicolor produce antibiotics late
cryptic antibiotic biosynthetic pathways. in their development, influenced by growth conditions, (B) a
crgA mutant exhibits precocious pigmented antibiotic produc-
2. Expression of a variety of heterologous cryptic pathways after their
tion, (C) the crgA mutant complemented with a functional copy
transfer to defined superhost antibiotic production strains.
of crgA introduced on a plasmid vector is delayed in antibiotic
3. Optimised expression of new antimicrobials, and engineered biosynthesis, (D) the crgA mutant containing the plasmid vector
variants thereof, derived from activation of cryptic pathways, without the gene, again exhibiting precocious antibiotic produc-
together with structural analysis and antimicrobial spectra. tion (provided by Ricardo Del Sol and Paul Dyson).
4.The establishment of refined genomic-based procedures for analysis
of metagenomes to identify new antibiotic biosynthetic pathways.
8. Generic antibiotic production superhosts derived by rational
5. Expression of a variety of metagenomic pathways after their transfer genomics-driven manipulation of Streptomyces coelicolor.
to defined superhost antibiotic production strains.
9. Refined superhosts strains optimised for production of key new
6. Optimised expression of new antimicrobials, and engineered antimicrobials.
variants thereof,derived from metagenomic pathways,together with
structural analysis and antimicrobial spectra.
7. Optimised expression of new combinatorial antibiotics, together
with structural analysis and antimicrobial spectra.

71
AMDR
Potential applications Centre for Microbial Biotechnology,Technical University of

The development of new technologies for antibiotic discovery and Denmark
production will benefit European SMEs in the biotechnology sector Department of Chemistry, University of Warwick, United
whose remit is to provide new antibiotics.Application of these new Kingdom
genomics-based procedures and technologies for discovery and
exploitation of natural products can provide a platform for a Department of Microbiology/Biotechnology, Eberhard
renaissance in drug discovery after 15 years of stagnation in this area. Karls-Universitt Tbingen, Germany
The pharmaceutical world market is estimated to amount to 506 Department of Pharmaceutical Biology, Eberhard Karls-
billion in 2004. Antibiotics represent one of the principal and Universitt Tbingen, Germany
indispensable groups of pharmaceuticals. Hence the project can help
to stimulate significant growth of European biotechnology SMEs. In School of Biomedical and Molecular Sciences, University of
addition, new antimicrobials discovered in the course of the project Surrey, United Kingdom
can potentially help alleviate the current crisis in the treatment of Dipartimento di biologia cellulare e dello sviluppo,
multiple drug-resistant pathogens. New antibiotics can provide Universita di Palermo, Italy
treatments of last resort for life-threatening diseases such as
tuberculosis and nosocomial infections. The efficacy of new Groningen Biomolecular Science and Biotechnology
antimicrobials will depend on subsequent rigorous testing for Institute, Rijksuniversiteit,The Netherlands
toxicity and side effects. However, even in the case of a product with Institut de Genetique et Microbiologie, Universit Paris-Sud,
significant side effects, the compound can provide a lead for the France
subsequent development of safe but effective derivatives, either by
chemical modification or by engineering biosynthetic modifications. Institut fr Chemie,Technische Universitt Berlin, Germany
Thus, there is the potential for these new antibiotics to make a major EntreChem SL, Mieres, Spain
impact on healthcare in the EU, both at the level of the individual
patient and also on healthcare budgets by reducing treatment times Departamento de Biologia Funcional, Universidad de
in hospitals. Oviedo, Spain
Institute of Biotechnology of Len, Spain
Institut National de la Recherche Agronomique,
Coordinator
Laboratoire de Gntique et Microbiologie,Vandoeuvre les
Dr Dyson, Paul Nancy, France
School of Biological Sciences Libragen,Villeurbanne, France
University of Wales Swansea, Institute of Microbiology, Seoul National University, South
Korea
Singleton Park,
Swansea SA2 8PP, United Kingdom
Phone: +44 1792 295667 Acronym: ActinoGEN
Fax: +44 1792 295447 EC contribution: 9 395 102
e-mail: p.j.dyson@swansea.ac.uk Duration: 60 months
Project web-site: www.swans.ac.uk/research/ActinoGEN/
Key words: antibiotics, actinomycetes, Streptomyces,
antibiotic resistance, genomics
Partners
Department of Molecular Microbiology, John Innes Centre,
Norwich, United Kingdom
Institute of Microbiology,Academy of Sciences of the Czech
Republic
Department of Chemistry, University of Manchester
Institute of Science and Technology, United Kingdom

72
VIRGIL AMDR
European vigilance network for the management

of antiviral drug resistance
Summary structured into interacting platforms that together will comprehensively
cover the problem of virus resistance to antiviral drugs.Being approach-
VIRGIL is the first European surveillance network capable of addressing rather than pathogen-based,the integration process and the generated
tools are flexible enough to embrace future drug resistance problems
current and emerging antiviral drug resistance developments in the field
related to other human virus infections. Until now, antiviral drug
of viral hepatitis and influenza. Focusing first on three major viral resistance has been determined by relying on single specialised
diseases, influenza, viral hepatitis B and viral hepatitis C, our strategy laboratories and high standard research groups that are often only
will be to build a sustainable, patient-oriented virtual institute on viral capable of addressing one particular aspect.The main objective of the
network will be to integrate clinical, technological and research
drug resistance by integrating the currently fragmented European networks and platforms that will interact in a coherent and synergistic
capacities into interacting subnetworks or virtual departments. Being manner, as each will provide a broad panel of specific tools for the
approach- rather than virus-based, one objective of the proposal is to others.The network will crystallise biomedical research on common
objectives targeting viral drug resistance that define specific activities
demonstrate a proof of concept that the network structure and the
and platforms. VIRGIL is structured into seven integrated platforms
integration process will allow us to easily embrace future drug resistance centred around the patients, each focusing on a topic contributing
problems related to other human viruses as well as to new drugs that towards the project objectives.
are currently under development and will come in general use during
the life-span of the network. Expected results
The creation of a European Network of Excellence on the antiviral
Problem drug resistance topic represents an opportunity to achieve real co-
operation among leading scientists in the field.This should significantly
Acute and chronic viral infections represent a major public health improve our knowledge on drug resistance. VIRGIL will fill the
problem in Europe and worldwide, responsible for a major socio- following gaps:
economical burden.The development of new antiviral drugs and new
diagnostic tools in the past decade has played a major role in the VIRGIL will integrate into a coherent network leading
improvement of patient care, treatment of viral diseases and has institutions expertise within Europe for antiviral susceptibility follow-
extended the quality and duration of human life. However, their up and testing.
increased use and misuse in medicine has given rise to viral drug VIRGIL will set up centralised databases to provide a unique
resistance leading to treatment failure and enhanced costs for health opportunity to track and model the emergence of resistance and
care and society. Furthermore, there is no global programme at its consequences for population transmission.
European scale to develop strategies for the surveillance and
containment of viral resistance to antiviral agents.Therefore, there is VIRGIL will create a unique EU antiviral resistance sample
a clear need to implement a European programme to optimise patient archive of serum and tissue samples and virus strains, which can
care and to minimise the emergence and spread of antiviral drug be used to test (anti)viral fitness/provide reference material for
resistance. testing new drugs on emerging ADR viral strains.
VIRGIL-IMPACT will provide information about costs,
Aim morbidity, viral evolution, drug use, geography and other
public health interventions, and can provide a model system for
The overall objective of the VIRGIL Network of Excellence is to set up other disease networks where antimicrobial resistance is an
the first-ever EuropeanVigilance Network capable of addressing current emerging problem.
and emerging antiviral drug resistance developments that will allow for
the management of this critical problem in Europe. Coordinated by VIRGIL-MODELS will establish a platform that is capable of analysing
INSERM (the French Institute for Health and Medical Research), the antiviral drug resistance in all its facets through the implementation
networks activities started in May 2004 with the initial task of integrating of in vitro systems (test tube or enzyme assays), cell culture
the fragmented European capacities and major expertise in the field systems, and in vivo animal models.
into a single coherent Network of Excellence.VIRGIL initially gathers VIRGIL-DRUGPHARM will allow the formulation of novel testable
55 organisations, including more than 60 academic laboratories and hypotheses when dissecting which factors contribute to drug
seven companies from 12 European countries.Focusing initially on three resistance in specific cohorts. In particular, pharmacokinetic para-
major diseases (viral hepatitis B, viral hepatitis C and influenza), its meters such as the dose and the treatment schedule of a
mission is to build a sustainable, patient-oriented virtual institute particular drug will be analysed.

73
AMDR
Microchip technology has already had a significant scientific

impact in cell biology but much less so in infection including virology. Coordinator
Therefore a successful outcome with early detection of drug-
Zoulim, Fabien
resistant mutations in influenza to anti NA and M2 drugs, or in viral
hepatitis B and C to new specific inhibitors would have a major INSERM Unit 271 and liver department
impact in a wide sense. Importantly the method could be applied to
Institut Universitaire de France
other viruses not at present in the network such as poxviruses,since
it is expected that smallpox will rapidly become a target for new 151 Cours Albert Thomas
antiviral molecules. It should also be possible to design chips to
69003 Lyon, France
detect entirely novel NA and HA molecules and in this manner the
network could also contribute to influenza pandemic planning. Phone: + 33 4 72 68 19 70
Fax: + 33 4 72 68 19 71
Potential applications E-mail: zoulim@lyon.inserm.fr
VIRGIL activities should result in an improved and standardised Project web-site: www.virgil-net.org
monitoring of drug resistance, with the development of new rapid
diagnostic tools and susceptibility testing. One achievement of the Key words: antiviral, drug, resistance, hepatitis, influenza,
VIRGIL network will be to establish correlations between the different flu, HCV, HBV, virus
clinical, genotypic and phenotypic analyses performed in expert
European laboratories to define new and internationally recognised Partners
standards for viral drug resistance testing. As an extension, the
network will ensure the spread of knowledge and technological 11 France
innovation in sites where a critical need for these technologies has
12 Germany
been identified, i.e. eastern and southern Europe. It will also foster
education and knowledge of health care providers and physicians 8 United Kingdom
regarding the optimal monitoring of drug resistance and up-to-date
2 Belgium
strategies that reduce the risk of selection of resistant viral strains.
Guidelines for clinical practice to monitor drug resistance but also 3 The Netherlands
for a rational use of antivirals will be generated and assessed. They
6 Italy
will take into account the diversity of social, political and economic
settings within Europe. Education programmes targeting patients and 4 Spain
the general population will be organised to encourage compliance to
1 Greece
medical monitoring and therapy through understanding of science.
Another objective of the VIRGIL network will be to constantly 2 Switzerland
evaluate new strategies to combat viral drug resistance.Therefore, it 1 Poland
will translate the results into new clinical trials for the optimal use of
drug resistance assays as well as for the evaluation of novel treatment 3 Sweden
strategies to prevent or overcome development of viral resistance. 1 Austria
To implement these strategies, partnerships with diagnostic and
pharmaceutical industrial partners within and beyond the actual 1 Israel
network will be launched.
Furthermore, all these actions should allow us to establish a stable
Acronym: VIRGIL
and long-lasting NoE at the European level with the capacity to Project number: LSHM-CT-2004-503359
rapidly and reliably determine resistance to new drugs and to EC contribution: 9 000 000
determine drug susceptibility of emerging viral strains under the Instrument: Network of Excellence
selective pressure of new treatments.This capacity to adapt and react Duration: 48 months
to new clinical situations based on the expertise of the teams and on
the possibility of including new partners during the duration of the
project will be a major characteristic of this network.This germ centre
will allow expansion and modification to create a network that can
cover virtually any viral infection for which antiviral drug resistance
is clinically relevant.

74
PNEUMOPEP AMDR
New methods of treatment of antibiotic-resistant

pneumococcal disease
Summary Aim
The innovations of this project are the new targets, identification of To identify lead compounds for the treatment of pneumococcal
disease by inhibition of the pneumococcal toxin, pneumolysin.
completely new lead compounds,a new approach to adjunctive therapy
To identify lead compounds for the treatment of pneumococcal
and a new method of delivery of the compounds. Streptococcus
disease by inhibition of the pneumococcal zinc metalloproteases.
pneumoniae imposes a huge disease burden on humans:it is the primary
To identify new methods for the delivery of the new anti-pneu-
cause of pneumonia and it is the second most common cause of
mococcal compounds.
meningitis. There is a pandemic of multi-drug resistant pneumococci
and treatment is compromised. Even if antibiotics kill the bacterium,
Expected results
they can fail to prevent death or neurological damage after meningitis,
Isolation and identification of peptides and/or small molecules as lead
due to the acute toxaemia.The first event in toxaemia is release of pro-
compounds for the treatment of pneumococcal disease.
inflammatory or toxic pneumococcal products, probably exacerbated
Use of the lead compounds,formulated in chitosan,for nasal delivery
by antibiotics. The pneumococcal toxin pneumolysin fulfils both of anti-pneumococcal drugs.
definitions: it is directly toxic to mammalian cells and it stimulates release
of inflammatory mediators from host cells.For this reason,and because
the toxin is essential for the survival of the bacterium in vivo,pneumolysin
will be a target of this project.A second target will be the cell surface Model of
pneumolysin
proteinases involved in adhesion and invasion, which are important
monomer
virulence factors for the pneumococcus.These proteins represent new
targets and their validation as targets has been done.The new treatment
will be based on binding peptides isolated from a series of large phage
display libraries or based on small molecules identified by high
throughput screening. Following screening of the phage libraries the
most promising peptides will be evaluated on the basis of binding affinity
and neutralising action in vitro.The peptides and small molecules will be
formulated in chitosan for nasal delivery.
Problem
This project is being undertaken in response to the need to find new
methods of treatment of disease due to Streptococcus pneumoniae.This
bacterium is a major cause of community-acquired pneumonia,
meningitis, bacteraemia and otitis media and it exhibits high rates of
multi drug-resistance in countries worldwide.
Peptide sequences specifically binding to pneumolysin or to metallo-
More than ever before, modern drug discovery is dependent on high-
proteinases (indicated as "Target" molecules in the picture) will be
throughput screening.Therefore,the drug discovery process is shifting
focus from identifying suitable candidate drugs which remains an identified through affinity selection on solid phase (microplates or
essential but time-consuming goal to identifying suitable lead magnetic beads) of several different phage displayed random pep-
compounds in order to maximise the cost-effectiveness and speed of tide libraries, having different length and level of constrain. Phage
the subsequent lead optimisation process. clones bearing specific peptide ligands will be isolated and the
sequence of the displayed peptide will be determined by sequenc-
ing of the corresponding single-strand DNA. Characterization of
biological properties of the selected peptides will be performed.

75
AMDR
The results from the project will lead to new treatments of Coordinator
pneumococcal pneumonia, meningitis and bacteraemia and new
formulations for delivery of treatment. Pneumococcal disease makes Prof.Andrew, Peter W
significant demands on health care systems but the rapidly increasing Department of Infection, Immunity & Inflammation
rate of antibiotic resistance in pneumococcal strains is impacting on
clinical management of pneumococcal disease. At one level the University of Leicester
project will confront this issue by producing new antimicrobial University Road
agents directed at hitherto unexploited targets. The project aims, Leicester, LE1 9HN, United Kingdom
however, to develop these new antimicrobial molecules targeted at
a single, highly important bacterial species rather than taking the Phone: +44 116 2522951
traditional approach of narrow- and broad-range antimicrobial drugs. Fax: +44 116 2525030
The use of targeted drugs is predicted to reduce the intensity of
Email: pwa@le.ac.uk
selection for any particular resistance mechanism since no selective
pressure is applied to species other than the target organisms, thus Project web-site: www.le.ac.uk/iii/eu/pneumopep
reducing the pool of organisms contributing to the spread of any Key words: antibiotic resistance, Streptococcus, pneumonia,
resistance mechanism. Reduction in the frequency of resistance will meningitis, pneumolysin, metalloproteinase
significantly prolong the shelf life of any antimicrobial drug. The
treatments developed from this project will also address the
toxaemia in pneumococcal disease that is not addressed by Partners
conventional antibiotics. The project will evaluate if a new drug Dr Oggioni, M R
delivery system based on chitosan will enhance the effectiveness of
anti-infective compounds. Dipartimento di Biologia Molecolare
Universit degli Studi di Siena
Policlinico Le Scotte (lotto 5; piano 1)
Siena, Italy
Prof.Teti, G
Dipartimento di Patologia e Microbiologia Sperimentale,
Universit di Messina
Messina, Italy
Dr Gill, I J
Bioanalytical Department
West Pharmaceutical Services Drug Delivery & Clinical
Research Centre Ltd
Nottingham, United Kingdom
Mr Jarosz,T
Essais Cliniques-Evaluation-Epidmiologie-Statistiques
Paris, France
Acronym: PNEUMOPEP
Duration: 36 months

76
AMIS AMDR
Antimicrobials
by immune stimulation
Summary Problem
AMIS aims to use the strength of our own innate immune system to The tremendous success with which antibiotics have been used to
combat infectious diseases is under serious threat from the increasing
design antimicrobial drugs for future generations.Antimicrobial proteins development of antimicrobial resistance. Without new treatment
in our immune system are often combined with inflammatory signals approaches to address antimicrobial resistance, this threat will
in one single molecule.AMIS will take that same approach and reshuffle continue to rise.To fight infectious diseases effectively in the future
we have to broaden the approaches in therapeutic intervention.There
different parts of different molecules to make novel effector molecules
are three ways by which the therapeutic intervention of infectious
that still have these combined functions but are optimally adapted for diseases can be broadened. The first is to design drugs that have a
therapeutic intervention. Within our innate immune system many smaller chance for resistance development (targeting evolutionary
conserved structures is one key element here).The second is to design
molecules have been identified over the last years that are involved in
drugs that are as different in mechanism of action as we can envision.
direct or indirect clearance of bacteria.The consortium will select the The third is to combine drugs. AMIS (Antimicrobials by Immune
most promising and innovative compounds with this dual mode of action Stimulation) combines these three strategies in a highly innovative
and: approach.
design proteins with anti-microbial activity in combination with an

Aim
inflammatory trigger, targeting extra cellular bacteria
Activators, receptors, effectors and inhibitors are an integral part of
design proteins with inflammatory priming capacity (without extra the complex mechanism of interaction in the innate immune system,
anti-microbial activity); targeting intracellular bacteria combining cellular stimulation and anti-microbial action. These
interaction mechanisms form the core focus of the research project
discover new modulators to dampen inflammation. envisaged by the consortium. The underlying theory is that the
multitude of triggers needed to get a full-blown immune response is
an intrinsic prerequisite to keep the process localised.That is why we
will aim at subtle immunostimulation or priming,which will,in bacterial
infections, be accompanied by an extra trigger, locally provided by the
bacterial products at the site of infection. In its pursuit of a novel
approach to address antimicrobial resistance, the consortium has
formulated three main research objectives.

77
AMDR
Expected results
Make an array of fusion proteins that combine strong antimicrobial with
inflammatory signals so that these two actions work in concert. By Partners
combining the best that we can find in our innate immune system we
Prof. Krnke, Martin
can tune the new molecules to perform better in certain specific
infections than Nature has provided so far.Furthermore we aim to learn Institute for Midical Microbiology, Immunology
from our innate immune system how to effectively recognise and kill a and Hygiene
bacterium for millions of years without developing major resistance. Medical Centre
University of Cologne
Potential applications Cologne, Germany
Prof. Espervik,Terje
The collaborative research in AMIS will lead to proof-of-principle for a
novel treatment approach to address antimicrobial resistance by Department of Cancer Research and Molecular medicine
combining the innate immuno-stimulation with the antimicrobial capacity Norwegian University of Science and Technology
of naturally occurring substances of the human innate immune system. Trondheim, Norway
Parts of that system have been proposed and tried before with
Prof. Peschel, Andreas
antimicrobial peptides from insects and other species and activation of
the immune system by bacterial compound [Toll Like Receptor (TLR) Faculty of Medical Microbiology, Cellular and Mollecular
ligands or small molecules that affect the signalling pathway of TLRs] as Microbiology Group
examples. However toxicity in the first example and over-activation of University Hospital Tbingen
the immune system combined with redundancy in the second example Tbingen, Germany
are inherent drawbacks in these alternative approaches.
Prof. Bjrck, Lars
Department of Cellular and Molecular Microbiology
Lund University
Lund, Sweden
Dr Haagsman, Henk P.
Department Public Health and Food Safety
Faculty of Veterinary Medicine
Utrecht University
Dr. Peter Antal-Szalmas
Department of Clinical Biochemistry and Molecular
Pathology
The consortium Medical and Health Science Centre
Debrecen, Hungary
Dr. Herman Groen
IQ Corporation
Coordinator
Groningen,The Netherlands
Dr van Strijp, Jos
Dr. Shai Yarkoni
Eijkman Winkler Institute
Target-In Ltd.
University Medical Centre Utrecht
Kfar-Saba, Israel
Heidelberglaan 100
3584 CX Utrecht,The Netherlands
Phone: +31 30 250 6528
Fax: +31 30 254 1770
E-mail: j.vanstrijp@azu.nl Acronym: AMIS
Key words: immunology, infections, novel antimicrobial EC contribution: 2 100 000
approach, immune stimulation, fusion com- Instrument: Specific Targeted Research Project
Duration: 36 months
pounds Starting date: 01/01/2005

78
PREVIS AMDR
Pneumococcal resistance epidemicity

and virulence an international study
Summary from this major ecological reservoir are widely spread in Europe and
in other parts of the world, threatening effective antibiotic therapy.
Human pathogens emerging in the contemporary environment face two For decades penicillin has been the drug of choice for treating
pneumococcal infections, but increasing levels of penicillin resistance,
main kinds of evolutionary challenges:
up to 50% in some areas, has resulted in the use of alternative
A. survival and growth in the antibiotic-rich milieu makes it essential antibiotics. However, this has led to the development of resistance to
many alternative antibiotics as well, and vancomycin is the last drug
that the bacteria acquire genetic traits of resistance of choice, especially when treating invasive pneumococcal infections
caused by DRPn clones, since vancomycin resistance has not been
B. successful drug-resistant strains must also be able to compete with
observed. Of major concern is the emergence and wide distribution
other members of the species for colonisation, geographic spread and of multiresistant isolates (those resistant to more than two different
disease in the human host. classes of antibiotics) globally, creating further treatment problems.
The main purpose of the programme PREVIS is to examine the interplay The PREVIS programme aims to address several major questions,
such as:
of these two challenges and also obtain insights on how host factors
Why do pneumococci sometimes act as devastating pathogens
and ecological/societal factors (antibiotic use, day-care centre
causing a severe disease with sometimes a fatal outcome, while in
attendance etc.) modulate the epidemiology of drug-resistant and drug- other instances cause a non-invasive upper respiratory tract
sensitive pneumococcal disease in diverse settings in northern,southern infection, or even just reside harmlessly in the nasopharynx without
and eastern Europe.PREVIS will provide an integrating platform to study symptoms of disease?
important and unexplored aspects of microbial and host factors related Are those pneumococci found among healthy children of the same
genetic lineages as those pneumococci causing invasive disease?
to pneumococcal disease/pathogenesis,epidemiology/transmission,and
molecular mechanisms for resistance development. A broadening of Are there differences in the severity and nature of diseases caused
by DRPn and drug susceptible (DSPn)?
knowledge on these issues should lead to improved and focused
How are transmissibility and virulence affected by antibiotic
treatment, prevention and intervention strategies towards these
resistance determinants?
common community-acquired infections.
Problem
Streptococcus pneumoniae remains among the most important causes
of life-threatening community-acquired diseases such as pneumonia,
septicaemia and meningitis, particularly in high-risk groups such as
young children, HIV-infected individuals and the elderly. The
introduction of penicillin and other antimicrobial drugs caused a
dramatic reduction in mortality of all pneumococcal diseases except
meningitis. However, pneumococcal disease attack rates have not
decreased and the annual global mortality rate of pneumococcal
disease is still estimated to be over one million deaths per year. In the
United States, pneumococcal infections remained a major cause of
potentially life-threatening diseases with fatality rates in a similar range
as those of AIDS,prostate and breast cancer.Streptococcus pneumoniae
is also a major cause of upper respiratory tract infections such as otitis
media and sinusitis.While these afflictions are seldom life-threatening
they are major contributors to health care costs and antibiotic use.
Not only is the human host the virtually exclusive target of pathogenic
pneumococci but the nasopharynx is also the main ecological
reservoir of this bacterial species. Up to 60% of healthy children
attending day-care centres were found to be colonized by S. Streptococcus pneumoniae
pneumoniae. Drug-resistant pneumococcal clones (DRPn) emerging

79
AMDR
Aim 6. identify novel approaches to the development of antivirulence drugs

7. identify the genetic/biochemical mechanisms of the fitness cost of
The main objective of PREVIS is to examine the interplay between
penicillin resistance and compensatory mechanisms that must exist
how pneumococci acquire genetic traits of resistance and how
in epidemic clones of DRPn
successful resistant and susceptible strains may cause colonisation,
transmission and disease,involving both bacterial virulence properties 8. identify the role of viral illness and immunological/genetic factors
as well as host factors. in the susceptibility of children to invasive pneumococcal disease
9. estimate the threshold levels of antibiotic consumption in the
Expected results community that select for resistance
1. determine the frequency and clonal types of DRPn and DSPn 10. develop a web-based data management infrastructure coupled
causing invasive disease and colonising healthy carriers with advanced machine learning tools for automated data-mining
of predictive associations.
2. clone- and serotype-specific estimates of disease potential for
invasive pneumococcal disease
3. using a microarray developed in PREVIS, from the two genome
sequences of TIGR4 and R6 and comparative genomics, we aim at Pneumococcal disease caused by both DRPn and DSPn results in a
identify factors involved in pneumococcal pathogenesis substantial portion of the estimated health care costs of infectious
diseases in Europe. Globally, mortality from pneumococcal diseases
4. whole-genome sequencing of a Streptococcus mitis strain, which
has remained among the highest of all infectious diseases. Yet this
is a frequent source of heterologous genes and gene fragments
potentially dangerous human pathogen also uses the healthy human
which may become building blocks of resistance determinants in S.
carrier as its global ecological reservoir. By gaining better knowledge
pneumoniae
about the spread of DRPn and DSPn, microbial and host factors
5. show whether antibiotic resistance determinants affect pathogen- important for pneumococcal pathogenesis, mechanisms for the
host interactions and identify host factors important for development of antibiotic resistance and the role of environmental
susceptibility to invasive pneumococcal disease factors such as antibiotic consumption for the emergence and spread
of antibiotic resistant pneumococci, we will create a platform for
improved treatment and more focused prevention and intervention
strategies.Also, as the prevalence of multi-resistant strains continues
to increase, creating further treatment problems, novel concepts for
making drugs are of major importance. In this project we intend to
develop lead substances for novel so-called anti-virulence drugs.If this
approach turns out to be successful we will have a new drug for
treating pneumococcal infections irrespective of whether or not the
bacteria are resistant to antibiotics.
Drug
resistance

80
AMDR
Coordinator Prof. Normark, Staffan

Dr Henriques Normark, Birgitta Microbiology and Tumorbiology Center
Department of Bacteriology Stockholm, Sweden
Swedish Institute for Infectious Disease Control Prof. Hakenbeck, Regine
Nobels vg 18 University of Kaiserslautern
171 82 Solna, Sweden
Kaiserslautern, Germany
Phone: +46 84752413
Prof.Wolf-Watz, Hans
Fax: +46 8302566
INNATE pharmaceuticals
E-mail: Birgitta.Henriques@smi.ki.se
Ume, Sweden
Project web-site: www.previs.net
Key words: Streptococcus pneumoniae, antibiotic Dr Gudnason,Thorolfur
resistance, molecular epidemiology, Directorate of Health-Infectious Disease Control.
pathogenicity, innate immunity
Seltjarnanes, Iceland
Partners Prof.Almeida, Jonas S
Dr Ekdahl, Karl Instituto de Biologia Experimental e Tecnolgica, IBET
Dept of Epidemiology Oeiras, Portugal
Swedish Institute for Infectious Diseases, SMI Dr Urbaskova, Pavla
Solna, Sweden National Institute of Public Health
Prof. de Lencastre, Hermnia Prague, Czech Republic
Instituto de Tecnologia Qumca e Biolgica (ITQB)
Oeiras, Portugal
Acronym: PREVIS
Prof. Spratt, Brian Project number: LSHM-CT-2003-503413
Imperial College London Instrument: Specific Targeted Research Project
Duration: 36 months
Department of Infectious Disease Epidemiology Starting date: 01/01/2004

Prof. Kristinsson, Karl G
Landspitali University Hospital
Reykjavik, Iceland
Dr Jonsdottir, Ingileif
Landspitali University Hospital,
Department of Immunology
Reykjavik, Iceland
Prof. Melo-Cristino, J
Laboratory of Microbiology
Faculdade de Medicina de Lisboa (FML),
Lisbon, Portugal

81
AMDR COBRA
Combating resistance to antibiotics by broadening

the knowledge on molecular mechanisms behind
resistance to inhibitors of cell wall synthesis
Summary A) Penicillin-binding proteins (PBPs) and critical associated
factors. The peptidoglycan is a complex structure, the synthesis
We aim at the elucidation of the molecular mechanisms of resistance of which involves multiple coordinated steps within and outside
of the cytoplasm. The complete disaccharide-peptide unit linked
to inhibitors of cell wall synthesis in bacteria responsible for severe
to the lipid carrier, once translocated through the cytoplasmic
nosocomial and community-acquired infections. Our STREP is focused membrane, is polymerised by protein complexes involved in cell
on -lactams, the major class of antibiotics in current clinical use, and elongation (elongase) and division (divisome). These complexes
include the PBPs (penicillin binding proteins) of classes A and B
on resistance due to modifications of the cell wall synthesising
that belong to the superfamily of the penicilloyl serine transferases
machinery and to production of -lactamases, the most prevalent and are the targets of the penicillins. According to the modules
mechanisms in Gram-positive and Gram-negative bacteria,respectively. they contain, they display D,D-transpeptidase, D,D-carboxy-
These studies will form a reference to globally assess the modifications peptidase and glycosyltransferase activities. Production of D,D-
transpeptidases that are inefficiently inactivated by the drugs,
of the structure, function, and dynamics of the peptidoglycan assembly commonly referred to as low-affinity PBPs, is the main mechanism
pathways responsible for emergence of resistance including the 3-D responsible for clinically relevant -lactam resistance in
structure of relevant components and possible targets. It will identify streptococci, staphylococci, and enterococci. Due to the
complexity of the peptidoglycan assembly pathway, analyses of the
new -lactamases,determine their 3-D structure and elucidate different mechanisms of resistance has been mainly limited to easily
aspects of the regulation of their gene expression and the mechanisms detectable modifications of the drug targets, such as the level of
responsible for their mobility. production of the PBPs and their interaction with -lactams.
However,recent analyses support the view that genes non-essential
for viability are required for expression of resistance mediated by
Problem low-affinity PBPs and other factors.Among these are:
Antibiotics are not like other drugs in that they act against bacteria (i) biosynthetic enzymes adding the side chain to the pentapeptide
and not the human host.Therefore the evolution of resistance under stem;
the selective pressure of antibiotics after exposure of populations
(ii) regulatory factors, that control as yet unknown responses of the
(human, animal) raises major therapeutical issues. This programme
bacteria to the drugs; and
addresses the general problem of resistance to antibiotics and
concerns the understanding of the mechanisms of resistance, in (iii) transglycosylases which appear to co-operate in an undefined
particular to inhibitors of cell wall synthesis.Among these are the - manner with the D,D-transpeptidase acitvity of low-affinity class
lactams, one of the most important classes of antibiotics, if not the B PBPs for peptidoglycan polymerisation in the presence of -
most broadly used antibiotics worldwide. The rates of -lactam lactams.
resistance for many common species found in infections have reached
In rare cases, mutations in these chromosomal genes have been
high levels in the community, as well as in the hospital.While in Gram-
detected in resistant bacteria but the extent of such modifications
positive organisms this resistance is mainly due to altered targets, in
and the role of the encoded protein are largely unknown. Analysis of
Gram-negative organisms, acquired resistance to -lactams is
the role of other components of the divisome and the elongase
essentially due to the presence of plasmid-encoded -lactamases or
complexes have not been developed since the metabolism of the lipid-
the over-expression of chromosome-encoded -lactamases.This latter
linked peptidoglycan precursors and their delivery to the
resistance can be enhanced by associated impermeability or efflux
polymerisation complexes is poorly understood.
mechanisms. Since many pathogens are multiresistant, there will be
an eventual limitation in the choice of antibiotics useful for primary B) -lactamases. Among clinical Gram-negative isolates, the major
treatment and therefore a promotion of a vicious circle facilitating mechanism of resistance to -lactam antibiotics is related to the
the emergence of new resistances. production of hydrolytic enzymes:the -lactamases.To counter this
problem, the pharmaceutical industry has marketed novel classes
of -lactams. However, the use of these new drugs was quickly
followed by the emergence of new -lactamases including those with

82
AMDR
expanded-spectrum activity many of which evolved from previous Gram-negative organisms. For several of these enzymes, gene
existing -lactamases.This process involved the three classes of - expression and the molecular basis of their dissemination will be
lactamases (classes A, C, and D) belonging to the superfamily of studied.The catalytic properties, the structure-activity relationships
penicilloyl serine transferases, that also includes the PBPs, and the and the 3D structure of some of them will be determined with regard
class B enzymes regrouping the metallo--lactamases (Zn++- to their activities against the antibiotics.The contribution of additional
dependent).While new enzymes are discovered almost every day factors, such as outer membrane permeability and efflux pumps, to
and have to be explored, the reason for the spreading of several high-level resistance to -lactams will be investigated in detail.
novel enzymes world-wide remains unknown and the factors
modulating their expression as well as the vehicles for mobility and
spreading of these genes have to be thoroughly studied. Expected results
Understanding the role of those amino acid residues in PBPs that are
essential for the expression of resistance and their contribution to the
Aim structure of the PBP D,D-transpeptidase domains.
This project focuses on the understanding of molecular mechanisms Understanding the biochemical role of the associated critical factors in
of resistance to -lactams and other cell wall inhibitors in clinical the pathway of peptidoglycan synthesis, their structure, and their role
Gram-positive and Gram-negative pathogens. We aim at studying in non -lactamase-mediated resistance; with respect to various
different enzymatic properties and structural features of class B PBPs regulators, and understanding the mechanisms by which they interfere
involved in -lactam resistance, as well as different auxiliary proteins, with the expression of resistance.
among which the class A PBPs and other enzymes involved in the
synthesis of substrate structures used by these class A and B PBPs. Understanding the diversity of the structures of the -lactamases
We also intend to find, in the cytoplasmic and in membrane steps of observed and studied, and understanding the role of the amino acid
the peptidoglycan synthesis,other critical factors,including regulators, residues essential for their catalytic properties.
interfering with the expression of resistance to cell wall inhibitors Understanding the genetic environment of the -lactamase genes and
and possible new resistance-conferring targets. The study of - its contribution to expression of resistance, gene dissemination as well
lactamases will include an extensive search for, and characterisation as the associated role of porins and efflux systems in the expression of
of, novel extended-spectrum -lactamases and carbapenemases in resistance.
3 D model of the chromosomal L2 -lactamase of Stenotrophomonas

maltophilia involved in -lactam resistance of a pathogen found in cystic
fibrosis and nosocomial infections.

83
AMDR
This programme addresses the general problem of resistance against Key words: resistance to antibiotics, cell wall synthesis-
a class of antibiotics widely used in the community and in hospitals. ing machinery, PBP, non-PBP factors and
Any progress, even the smaller ones, in the understanding of these resistance, -lactamases, catalytic mecha-
mechanisms will be of benefit to academia, public health and industry. nisms, structural studies, gene acquisition
It will increase our knowledge of insufficiently explored and new and mobility, Gram-positive and Gram-nega-
mechanisms of resistance toward cell wall inhibitors. It will lead to tive organisms.
the deciphering and the discovery of novel mechanisms including the
role of several auxiliary proteins involved in resistance.The isolation
of -lactamases, PBPs and other components essential for the Partners
expression of resistance to -lactams and other cell wall inhibitors, Centre dIngnierie des Protines, Lige, Belgium
reinforced by knowledge of their 3-D structure, will allow for the
future setup of assays to screen for new inhibitors and will improve Department of Sciences, Swammerdam Institute for Life
drug design.The knowledge of the sequence of different targets will Sciences, Molecular Cytology,Amsterdam,The Netherlands
be used to create databases containing new -lactamases and new Microbiology, University of Kaiserslautern, Germany
PBP alterations linked to resistance. Particular mutations responsible
for resistance could then be used to develop sequence-based Medical Microbiology, Zrich, Switzerland
molecular diagnostic tools. Discovery of novel mechanisms of Regulation of gene expression/Centro de biologia molec-
resistance will result in the identification of new phenotypes helpful ular severo ochoa, Campus universidad autonoma,
for the detection of resistance in clinical laboratories.This will aid in Madrid, Spain
the interpretation of susceptibility and resistance to different classes
of cell wall inhibitors, in particular -lactams. Biochemistry/Universit Paris XI / IBBMC, Orsay, France
Finally,transmission and acquisition of resistance by new strains is one Department of Chemistry, University of Warwick, United
of the major factors in resistance dissemination.A better knowledge Kingdom
of these mechanisms should facilitate the recognition of the antibiotics IBS, Institut de Biologie Structurale, Grenoble, France
most powerful in selecting for the mechanisms studied.Understanding
of the transmission mechanisms is a crucial step in preventing Bacteriology, University Paris XI, Le Kremlin Bictre,
resistance as well as in guiding optimal antibiotic usage. France
Servicio de Microbiologia, Hospital Universitario Ramon
y Cajal, Madrid, Spain
Antibiotic Resistance Monitoring & Reference
Laboratory, London, United Kingdom
Coordinator Molecular Microbiology, National Institute of Public
Health,Warsaw, Poland
Prof. Gutmann, Laurent
Department of Pathology and Microbiology, University of
Microbiologie
Bristol, United Kingdom
INSERM EMI0004 Universit Paris VI,
Dipartimento di Biologia Molecolare, Sezione di
Laboratoire de Recherche Molculaire sur les Antibiotiques Microbiologia, Siena, Italy
15 rue de lcole de Mdecine Inserm Transfert SA, Paris, France
75270 Paris CEDEX 06, France
Phone: +33 1 42 34 68 62
Fax: +33 1 423 25 68 12 Acronym: COBRA
E-mail: laurent.gutmann@hop.egp.ap-hop-paris.fr; EC contribution: 2 980 000
gutmann@ccr.jussieu.fr Instrument: Specific Targeted Research Project
Duration: 36 months
Project web-site: http://www.antibior.com Starting date: 01/02/2004

84
micro-MATRIX AMDR
Workshop on strategies to address antimicrobial

resistance through the exploitation of microbial
genomics
Recent genomic technologies allow the study of global physiological pro- The workshop conclusions will be centred on proposing to the
European Commission a realistic roadmap to implement a research
cesses in microbes.Their application to the study of pathogens allows activity based on functional genomics to tackle the problem of
improved searches for new medicines to combat infection and to better antibiotic resistance and discovery with sufficient industrial, clinical
avoid the emergence of resistance against them. It will also help to and academic participation to guarantee its long term success.
anticipate therapies for new emerging diseases and to devise treatments
to help individual patients to overcome each infection. Predictive Potential applications
microbiology,based on genomic analysis,may also be used to anticipate How genomics can help to combat antibiotic resistance?
the presence of unexpected potential pathogens. Both industrial and Genomics has been applied to identify new inhibitable bacterial
sustained public sector efforts are needed to fully develop the promising targets, but it can be used as well to gain valuable knowledge on how
potential of this research frontier of the microbial world. bacteria behave during infection, how they respond when their
proliferation is challenged or when they are treated with an antibiotic.
Problem Target identification

The discovery of new antibacterial agents against resistant micro- Comparative genomics yields information on the universality of
organisms is an urgent and vital need. All EU member states targets in important pathogens. Moreover, it identifies those genes
unanimously agreed that antimicrobial resistance was no longer just that being absent in humans and animals are less likely to produce
a national problem, but a major international issue requiring a problems when their function is blocked. A recent genomic search
common strategy at European level (The Copenhagen comparing the genomes of three important pathogens, Haemophilus
Recommendations Report from the European Union Conference on The influenzae,Streptococcus pneumoniae and Staphylococcus aureus indicates
Microbial Threat, September 1998, 1). Recommendations released that more than 350 bacterial genes are possible targets (Payne, D. J.
following this meeting expressed four important issues, among them Microbiology Today, 2004, 31: 55-57). After finding that a gene may be
the need to carry out research to fight the problem of antimicrobial a target, further work is required to obtain information on what
resistance. specific property or domain of the encoded protein is the one that
can be successfully inhibited. A substantial amount of additional
The social costs incurred by the incidence of infectious diseases in
research may still be needed before an assay for HTS (high throughput
the population at large,and in particular the elderly and the productive
screening) can be devised and validated.
age sectors,are enormous.Hospitalisation costs per patient run above
about 500 per day. Curbing the spread of resistant pathogens will
The future of genomics in target identification
result in the attainment of high standards in human health care,a main
component of the quality of life, as a clear priority for the European Genomics can help to refine and validate targets by analysing changes
Union. It will reduce social and public healthcare costs and will in the expression of genes that take place in the microbes when they
therefore have a beneficial impact on the citizens of the EU. Specifically are subject to stressful conditions that mimic the environment
it is anticipated that the ability to effectively treat microbial infections confronted during the process of infection.
will reduce morbidity, and have a positive impact on health Progress in molecular modelling and in the synthetic skills needed for
management policies of the EU member states. mimicking protein surfaces are still required to fully exploit the
knowledge derived from the study of the interactome. In the future
Aim the study of the interactome will identify the precise domains in some
target molecules that are required for the function of proteins that
To discuss microbial functional genomics as a powerful and innovative establish interactions required for the survival of the pathogen and
tool to discover new cellular targets that will be used to counteract for its interaction with the host. If suitable mimics are synthesised
bacterial resistance to antibiotics and to further avoid the generation they can be used as scaffolds to build an altogether new class of
and spread of new resistances. bacterial inhibitors.

85
AMDR
How to avoid the path to resistance

Pathogens become resistant to antibiotics by synthesising new proteins Coordinator
or modifying part of their physiology. In most cases the acquisition of
Vicente, Miguel
resistance makes resistant bacteria less efficient to compete against their
non-resistant relatives in the absence of the antibiotic.This extra burden Centro Nacional de Biotecnologa CSIC
can in turn be minimised by the acquisition of compensatory mutations Campus de Cantoblanco
that counterbalance the decrease in fitness. Compensatory mutations 28049 Madrid, Spain
are difficult to revert and contribute in some cases to maintain a
Phone: +3491 585 4699
proportion of resistant individuals within pathogen populations
(Andersson, 2003, Persistence of antibiotic resistant bacteria, Current Fax: +3491 585 4506
Opinion in Microbiology 6: 452-456). Email: mvicente@cnb.uam.es
Resistance is both inheritable and transmissible. Blocking the Project web-site:
horizontal transfer of resistance,although of limited therapeutic value, For the book of abstracts:
is a possible way to prevent the spread of antibiotic resistance to the http://www.cnb.uam.es/~mvicente/full_book.pdf
susceptible pathogen populations.
For the final report:
Functional genomics supplies data on how bacteria respond to http://www.cnb.uam.es/~mvicente/micro-
different environments by adjusting the rates at which different genes MATRIX+cover.pdf
are transcribed. We can therefore obtain a global picture of the
Key words: bacteria, essential functions, regulation,
changes that occur in bacteria when they are treated with an antibiotic
gene expression, stress response, patho-
lead and deduce the likelihood of resistance emergence before the
genesis
lead is further developed into a medicine.This will not only save efforts
on compounds that are prone to elicit resistance but will also provide
information on how to anticipate resistance and devise procedures Partners
to circumvent it before a new antibiotic is in clinical use.
Tel Aviv University, Israel
Genomics of the antibiotic producers ITQB Universidade Nova de Lisboa, Portugal
Institute of Cell & Molecular Biology, University
One topic in which genomic research can help is the analysis of global
of Edinburgh, United Kingdom
regulatory circuits in the antibiotic-producing organisms.Many efforts
have been put into the application of genetic research to increase the Institut Pasteur, France
amount of antibiotic produced by the producer organisms. Most if PROGENIKA Biopharma S.A., Spain
not all of them have not yielded practical results.
Many antibiotics are produced under suboptimal growth conditions
as products of secondary metabolism. Under those conditions
Acronym: micro-MATRIX
deviations towards the production of a single compound may severely
upset the growth of the organism, resulting in a failure to increase EC contribution: 2 980 000
the net production of the desired compounds. A better understanding Instrument: Specific Support Action
of the regulatory circuits that operate under suboptimal and stressful Duration: Four days
conditions will allow the modification of the production of some
secondary metabolites without greatly disturbing growth.
Diagnostics
DNA arrays can speed up the diagnosis of infections.Moreover,the use
of subgenomic arrays containing suitable sets of genes will easily identify
specific strains of a pathogen. Once the technology is fully developed
it will be possible to design antibiotic courses specifically tailored to
help an individual patient to fight against one particular infection.

86
Brain,
neurological
and psychiatric
diseases
PROMEMORIA 88
NEWMOOD 90
APOPIS 93
GENADDICT 95
EUROSCA 97
NeuroNE 100
BrainNetEurope II 102
AUTISM MOLGEN 106
SYNSCAFF 108
EUROHEAD 111
SPASTICMODELS 113
NCL-models 116
X-ALD 120
PainGenes 122
GRIPANNT 124
STRESSPROTECT 126
INTERDEVO 129
EUROMEMO 132
ESNI course 2003 135
FENS Forum 2004 137
RABRE 139
BRAIN, NEUROLOGICAL PROMEMORIA

AND PSYCHIATRIC
DISEASES
From cell-cell recognition to memory formation.

New strategies for the treatment of dysfunctional
plasticity, learning and memory
Summary corresponding drug targets.The study of the role of neuronal CAMs
has so far been limited by technological problems and functional
The PROMEMORIA project focuses on the role of cell recognition investigations have been difficult. However, we have recently
developed the first series of peptido-mimetics of a neuronal
processes in normal and dysfunctional plasticity, learning and memory
CAM (NCAM) and thereby created a new type of compound with
with the aim of developing compounds with a beneficial effect on a tremendous promise both as regards the understanding of the
diseases involving cognitive impairment. The focus on neuronal cell functions of CAMs at the molecular level and the development of
drugs with beneficial effects on synaptic plasticity on
adhesion molecules is novel and unique. Recent research has shown
neuroregeneration.
that these molecules play key roles in learning and memory.The project
Neuronal cell adhesion molecules
includes a series of subprojects focused on gene discovery, structural
biology, synaptic plasticity at both the physiological and morphological Neuronal CAMs are known for their involvement in brain
developmental processes,and recent evidence now indicates that they
level, and a number of models of deficient plasticity, learning and also participate in synaptic alterations in connection with memory
memory. formation in adults. CAMs of particular importance include member
of the Immunoglobulin-(Ig) superfamily, Cadherins and Integrins.
The Consortium consists of 18 leading teams from 11 countries, of Particularly the roles of L1 and NCAM are now well supported by
which two are new EU member states. It is composed of 14 academic experimental data.Neuronal CAMs in general are well known for their
partners and 4 SMEs. The Consortium contains teams specialised in involvement in processes of relevance to neuronal plasticity such as
axonal extension and guidance,cell migration,differentiation,survival,
genetics, protein chemistry, neurophysiology, neuroanatomy, and formation of synapses.
neurobiology, animal models of learning and behavior, in vivo test
Role of CAMs in memory formation
systems for a very broad range of behaviour and learning phenomena.
Evidence for a role of L1 and NCAM in memory formation comes
Moreover, there is a considerable expertise in drug screening and from studies interfering with the functions of these molecules in
development. different learning paradigms. Modifications of L1- and NCAM-
mediated cell recognition appear to be a prerequisite for the
An efficient dynamic management structure is proposed with four key formation of stable changes in synaptic communication.These changes
objectives:integration of research results and early identification of new are probably achieved through alterations in gene expression, post-
findings; training of future world leaders in this research area; translational modulations and turnover of the proteins.
dissemination of results to scientists, patients and the general public;
the issue of 5-10 patents securing protection and transfer to European Aim
industry of PROMEMORIA discoveries. to achieve a better understanding of the role of neuronal cell
adhesion molecules CAMs in the maintenance and modulation of
synaptic and network plasticity and in cortical circuitry and
Background information processes underlying learning and memory;
Cognitive impairment to develop and validate a series of suitable animal models for studies
In the western world, 6-10% of adults older than 65 years have of memory function and dysfunction in diseases;
dementia mainly due to Alzheimers disease. A large group of to search for novel ligands and mimetics of neuronal CAMs for
elderly are suffering from so-called mild cognitive impairment, a modulation of plasticity with the aim of developing therapeutics
diagnostic term applied to individuals who do not meet the clinical improving learning and memory
criteria of dementia or Alzheimers disease, but who are cognitively
impaired.
The therapeutic possibilities for treatment of cognitive
impairment are currently very limited, emphasising the profound
need for development of new therapeutic modalities.A problem is
the heterogeneous temporal and spatial distribution of the

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AND PSYCHIATRIC
DISEASES
Expected results
The Consortium expects to discover new genes and proteins,identify
novel pathogenic mechanisms and define new therapeutic strategies,
with clearly defined deliverables:
Coordinator
new counterreceptors (ligands) of cell adhesion mole- Prof. Bock, Elisabeth
cules will be identified, key proteins will be structurally char- University of Copenhagen
acterised and binding sites will be localised (WP 1);
Institute of Molecular Pathology
experts in the field of neurophysiology will establish the role of
neuronal CAMs in maintenance and modulation of select- The Protein Laboratory
ed synapses and synaptic populations. Moreover, the role of Blegdamsvej 3C
CAM signaling in triggering use-dependent and/or developmental
changes in circuitry will be assessed (WP 2, 3, 8); 2200 Copenhagen N, Denmark
new animal models for dysfunctional plasticity will be estab- E-mail: bock@plab.ku.dk
lished, validated and employed for evaluation of learning and Project web-site: Under construction
memory under various conditions involving CAM-modulation
(WP 4, 5, 6, 7); Key words: genetics, cell adhesion molecules, cognition,
dementia, neurodegeneration, drug dev-
ligands will be developed interacting with the CAM binding elopment
sites, either agonistically or antagonistically, through drug screen-
ing or based on structural determinations. These studies are
expected to identify novel therapeutic strategies and new thera- Partners
peutic targets (WP 8); 1 Ireland
the unprecedented degree of collaboration between academic 2 United Kingdom
groups and biotechnology SMEs in PROMEMORIA is expected to
result in a rapid translation of findings into new strong intel- 1 France
lectual property, and subsequently into drug screening pro- 2 Germany
grammes (WP 10, 11);
2 Switzerland
the goal-oriented network will train a younger generation of
European scientists to excellence within the highly integrated 2 Spain
research area of plasticity, learning and memory (WP 9); 1 Poland
at least five patent applications will be filed (WP 10). 2 Sweden
1 Israel
2 Denmark
A considerable fraction of adults will encounter impairment in
1 Estonia
learning and memory as they age, and age-related memory impair-
ment often predates more serious neurological problems.
Neurodegenerative diseases including Alzheimers disease,
Parkinsons disease, motor neuron diseases, stroke and demyelinat-
ing diseases are rapidly becoming major health problems in devel-
oped countries. Moreover, neurological injuries also may lead to Acronym: PROMEMORIA
cognitive impairment. Project number: LSHM-CT-2005-512012
Duration: 48 months

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BRAIN, NEUROLOGICAL NEWMOOD

AND PSYCHIATRIC
DISEASES
New molecules in mood disorders: a genomic,

neurobiological and systems approach in animal models
and human disorder
Summary Furthermore, there has been a remarkable increase in the rate of
suicide in young males over the last 15 years in the EU. Indeed suicide
This is a major collaboration between 13 clinical and basic science is second only to road traffic accidents as the cause of death in the
15 to 25 age band. Female gender and social and familial factors
groups in 10 EU countries which addresses the evident need to
increase risk of depression but little is known about how these
discover: influences work in the brain, least of all at the molecular level.
Antidepressant treatment has improved in terms of tolerability and
new molecular mechanisms in the causation of depression thus treatment adherence but drugs currently in use have the same
primary mechanisms of action as 30 years ago and their downstream
new molecular mechanisms of effective drug-treatment.
molecular actions are obscure. Furthermore, at most 65% of new
We will measure three fundamental processes underlying depression episodes respond to drug-treatment and chronic, treatment-resistant
depression is a major health burden.
the inability to experience pleasure,excessive sensitivity to stress and
negative appraisal of circumstances.This will enable us to cross-validate
findings in humans and animal models. In animals (rats and mice) we
Aim
will use a mixture of well-established and novel methods for inducing The aim of this proposal is to combine new functional genomic
technologies with chemical analysis in an integrated multidisciplinary
genetic and mild stress-related changes in the three processes.We will
approach both to exploit hitherto overlooked genetic resources for
detect the molecular mechanisms involved by creating the new antibiotics and, secondly, develop generic superhosts to
NEWMOOD microarray chip and measuring changes in gene produce these new antibiotics in high yields. ActinoGEN proposes
three parallel objectives to discover and develop new antibiotics
expression. Changes which are consistent across many models will
based on exploiting the genetic resources of actinomycetes, hitherto
become targets for new treatments. In addition we will search for the major source of existing antimicrobials.The first of these is to
neurochemical changes in how monoamine and other neurones are activate cryptic antibiotic biosynthetic pathways. Recent genome
regulated which are shared by the models.These too will become new sequencing projects have revealed a genetic potential for
actinomycetes to produce many more antibiotics than previously
molecular targets. recognised.ActinoGEN will explore how different cryptic pathways
can be activated and then determine the structures and activities
Humans with varying genetic and environmental risk factors will be
of the resulting new antimicrobials. The second approach will rely
compared on the three behaviours and on the brain systems and on the discovery of new antibiotic biosynthetic pathways from
neurotransmitters responsible using functional magnetic resonance diverse actinomycetes. The number of actinomycete species that
imaging.Gene-expression in the human postmortem brain will provide have been isolated to date represents a small fraction of the total
in the environment. ActinoGEN will exploit the untapped genetic
further validation of animal findings and targets for treatment. resource of as yet uncultured species to obtain antibiotic
biosynthetic gene clusters that can direct synthesis of new
Background antimicrobials. A third route to new antimicrobials is by
combinatorial biosynthesis. Biosynthetic genes from both new and
Unipolar major depression is common and a leading cause of existing pathways will be combined to direct synthesis of new
morbidity and mortality.In developed countries it is twice as common antibiotics with predicted structures. The design of new hybrid
in women as men, affecting 20% of women at some time in life.The molecules will be related to improving antimicrobial activity. A fourth
global burden of disease survey found it will be the fourth most major aim, underpinning the Drug Discovery objectives, is the
prevalent cause of disability-adjusted life years, accounting for about engineering of generic Superhosts for antibiotic production.A rate-
20% of the burden of disease (Murray 1997 Lancet 349:1436-1442). limiting step to developing a new antibiotic is yield improvement.
This is greater than the burden of common causes of death such as Post-genomic analysis permits, for the first time, a concerted and
cardiovascular disease. In addition to its economic consequences, holistic approach to engineering generic Superhosts for use in the
depression is a direct cause of death through suicide. There are production of high yields of a wide variety of antibiotics.As part of
important cohort effects the age of onset of depression is steadily ActinoGEN, this complementary activity is vital to greatly accelerate
decreasing each decade and it is no longer a disease of middle age. the discovery and development of new drugs.

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Expected results
The overarching aims are to identify:
Coordinator
Prof. Deakin, Bill
new molecular mechanisms in the causation of depression,
specifically new candidate genes for diagnosis, prognosis and University of Manchester
treatment choice;
Neuroscience and Psychiatry Unit
new molecular mechanisms of effective drug treatment, specifically
Room G.907, Stopford Building
new molecular targets for antidepressant drugs and novel candidate
drug treatments. Oxford Road
The technical aims are to: Manchester, M13 9PT, United Kingdom
create a web-based core data-set of behavioural and neurobiological Phone: +44 161 275 7427
variables common to human and animal vulnerability to the
Fax: +44 161 275 7429
depression endophenotype;
E-mail: bill.deakin@man.ac.uk
create a new tool for research in depression: the NEWMOOD
Depression microarrays; Project web-site:
define a human pharmaco - fMRI signature for antidepressant NEWMOOD website within http://projectplace.com
efficacy;
A public website will be created.
disseminate new and harmonised standards of research in affective
Key words: depression, stress, candidate genes, human,
disorders.
animal models, brain, neurochemical,
neurobiological, neurotransmitters, anti-
Expected results depressants, 5-HT
the identification of differences in gene expression that are

consistent across a wide range of entirely different animal models; Partners
the detection of altered gene expression, neurochemical, Dr Lanfumey, Laurence
neurophysiological and neuroendocrine regulatory mechanisms,
INSERM U 288
which are common to a range of genetic, developmental and
mechanistic animal models of vulnerability; Facult de Mdecine Piti-Salptrire
the identification of candidate genes for diagnosis, prognosis and Paris, France
treatment choice;
Prof. Corradetti, Renato
a better understanding of the molecular mechanisms of depression
and other mood disorders; Universit degli Studi di Firenze,
a greater understanding of the nature and extent of genetic Dipartimento di Farmacologia Preclinica e Clinica
predisposition in depression. Florence, Italy
Prof. Lesch, Klaus Peter
University of Wrzburg
the identification of new targets for drug therapies;
Department of Psychiatry and Psychotherapy
the development of novel drug treatments;
Wrzburg, Germany
progress towards drug regimes tailor-made to suit individuals;
Prof. Maldonado, Rafael
ultimately, to reduce the overall morbidity and mortality due to
depression and other mood disorders. Universitat Pompeu Fabra
Laboratory of Neuropharmacology
Department of Experimental Sciences and Health
Barcelona, Spain

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DISEASES
Prof. Harro, Jaanus Dr Hkfelt,Tomas

University of Tartu Karolinska Institutet,
Department of Psychology Department of Neuroscience B3:4
Estonian Centre of Behavioural and Health Sciences Stockholm, Sweden
Tartu, Estonia Prof. Del Ro, Joaqun
Prof. Steinbusch, Harry University of Navarra Medical School
University of Maastricht Department of Pharmacology
Division Neuroscience Pamplona, Spain
Maastricht,The Netherlands Dr Swiergiel,Artur H
Prof. Bagdy, Gyorgy Polish Academy of Sciences ("IGAB")
Head of Laboratory of Neurochemistry and Experimental Institute of Genetics and Animal Breeding
Medicine
Poland
National Institute of Psychiatry and Neurology,
Budapest, Hungary
Dr Kelly, Paul A T Acronym: NEWMOOD
University of Edinburgh EC contribution: 7 200 000
Division of Clinical Neurosciences Duration: 60 months
School of Molecular & Clinical Medicine
Western General Hospital
Edinburgh, United Kingdom
Dr Sharp,Trevor
University of Oxford
Department of Pharmacology

92
APOPIS BRAIN, NEUROLOGICAL

AND PSYCHIATRIC
DISEASES
Abnormal proteins in the pathogenesis

of neurodegenerative disorders
Summary
Degenerative disorders of the nervous system including Alzheimers and
Parkin-sons are among the most de-bilitat-ing illnesses. There is
currently no treatment that can halt or prevent,let alone reverse nerve
cell degeneration. One hallmark common to these dis-orders is the
deposition of abnormal protein aggregates. APOPIS is designed to
elucidate the role of abnormal proteins in the pathogenesis of
neurodegenerative disorders and to develop methods for early
diagnosis and treatment of these devastating diseases.
Senile plaque associated markers in SweArc APP transgenic mice.
Astrogliosis (strongly stained) around senile plaques (white arrows).
Background Lars Nilsson, Uppsala University
The APOPIS programme is based on the information generated by
the recently completed sequencing of the human genome. APOPIS
will make use of this information and employ state-of-the-art Aim
technologies in functional genomics, proteomics, bioinformatics, and
The first goal of APOPIS is to improve the understanding of the
neuroimaging, which will be combined with more traditional
pathogenic mechanisms involved in neurodegenerative diseases applying
approaches such as epidemiological studies, transgenic model
several complementary model systems and methodologies.The second
organisms and combinatorial chemistry in order to quickly identify
goal is to advance the early clinical detection of these diseases, thus
putative target genes and lead compounds for drug discovery.
providing a theoretical chance for clinical treatment before it is too late.
The third goal of APOPIS is the development of effective strategies and
efficacious drugs for the treatment and the prevention of these diseases.
Expected results
APOPIS is designed to elucidate disease mechanisms and to translate
the results into clinically useful products. Protein deposits seem to play
an essential but as yet poorly understood role in disease progression.
Therefore, by comparing a whole set of neurodegenerative diseases
afflicting different areas of the brain, it is expected to gain insight into
common features in the underlying disease mechanisms, for instance,
the causative agents or events for abnormal protein aggregation.These
breakthrough discoveries will lead to the identification of
pharmacological targets creating the basis for an effective drug design
to halt the cascades involved in the disease processes.
The advancement in clinical studies will lead to improved tools for the
early and differential diagnosis of neurodegenerative diseases.Immediate
and reliable detection of neurodegenerative disorders is a prerequisite
Senile plaque pathology differently stained for efficient clinical studies and finally for a successful treatment of the
in SweArc APP transgenic mice (A, B). Lars Nilsson, disease. Intellectual property rights will be protected by patent
Uppsala University applications to ensure the seamless design and development of efficacious
and safe clinical products for the treatment and the prevention of
neurodegenerative diseases.

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Coordinator Department of Public Health and Caring

Prof.Adlkofer, Franz Sciences/Geriatrics, Uppsala University, Sweden
VERUM Foundation Institute of Biochemistry, Swiss Federal Institute for
Technology, Zurich, Switzerland
Pettenkoferstr. 33
Department of Neuroscience, Universita Vita-Salute San
80336 Munich, Germany Raffaele, Italy
Phone: +49 89 5309880 Istituto de Recerca Biomedica de Barcelona, Parc Cientific
Fax: +49 89 53098829 de Barcelona, Spain
E-mail: prof.adlkofer@verum-foundation.de Phone: +34 9340 34902, fax: +34 9340 37225
Project web-site: www.verum-foundation.de/apopis Division of Psychiatry Research, University of Zurich,
Key words: early diagnosis, genetics, neurodegenerative Switzerland
disorders, pathogenesis, protein aggregation, Clinic of Neurology, University of Marburg, Germany
therapy EVOTEC NeuroSciences GmbH, Hamburg, Germany
Dementia Research Centre/The National Hospital for
Partners Neurology and Neurosurgery, University College London,
Institute of Neurosciences, Swiss Federal Institute of United Kingdom
Technology Lausanne (EPFL), Switzerland School of Medicine, University of Genova, Italy
Institute of Neuropathology, University Hospital Zurich, Department of Biochemistry at the University of Naples,
Switzerland Italy
Bioinformatics and Molecular Genetics, University of Institut fr Organische Chemie, Universitaet Darmstadt,
Freiburg, Germany Germany
Wallenberg Neuroscience Centre, Lund University, Institute for Clinical Neurobiology, University of
Sweden Wrzburg, Germany
Groupe Hospitalier Piti-Salptrire, Institut Nationale de Structures & Biocomputing, European Molecular Biology
la Sant et de la Recherche Mdicale (INSERM), Paris, Laboratory, Heidelberg, Germany
France Department of Neurology PO 41/Institute of Psychiatry,
Universit de Lille 2, France Kings College London, United Kingdom
Institut de Pharmacologie Molculaire et Cellulaire, MPI of Molecular Cell Biology and Genetics, Max Planck
Centre National de la Recherche Scientifique,Valbonne, Society for the Advancement of Science, Dresden,
France Germany
Centro de Biologia Celular/Laboratory of Neuroscience, Institute of Biochemistry, University of Zurich,
Universidade de Aveiro, Portugal Switzerland
Flanders Interuniversitary Institute for Biotechnoology, Biological Chemistry/Institute of Life Sciences,
Center for Human Genetics, Leuven, Belgium The Hebrew University of Jerusalem, Israel
Cavalieri Ottolenghi Scientific Institute, Fondazione Department of Neurology, University of Cambridge,
Cavalieri Ottolenghi, Italy United Kingdom
Cellzome AG, Heidelberg, Germany Department of Biosciences, University of Kent at
Department of Human and Animal Physiology, University Canterbury, United Kingdom
of Athens, Greece Department of Molecular Genetics at the University of
Department of Biochemistry, University of Munich, Antwerp, Flanders Interuniversitary Institute for
Germany Biotechnology,Antwerp, Belgium
Division of Psychiatry Research, University of Zurich, Neuroproteomics Research, Max Delbrueck Center for
Switzerland Molecular Medicine, Berlin, Germany
Department of Neuropathology, University of Basel,
Switzerland
Acronym: APOPIS
MPI for Neurobiology, Max Planck Society for the Project number: LSHM-CT-2003-503330
Advancement of Science, Martinsried, Germany EC contribution: 8 995 518.39
Laboratory of Neurodegeneration, International Institute Duration: 36 months
of Molecular and Cell Biology,Warsaw, Poland Starting date: 01/01/2004

94
GENADDICT BRAIN, NEUROLOGICAL

AND PSYCHIATRIC
DISEASES
Genomics, mechanisms and treatment of addiction

Summary are responsible for predisposition to addiction.Their complementary
molecular genetics and neuroscience expertise provides a critical mass
Addiction is a brain disease, common in Europe, with deleterious of expertise to create a foundation of genetic information using state-
of-the-art mouse models. These academic groups have linked with an
consequences on individual physical and psychological health,and serious
Icelandic company,Decode Genetics,which is at the forefront in Europe
societal and economic consequences through criminality and violence, in the field of complex genetics in man.They bring a human research
decreased productivity and increased healthcare costs. In every family, contribution to this Integrated Project of equivalent capacity to the
in a lifetime one can identify someone who has suffered from addiction. animal studies.The human experiments bring a unique and well-defined
human population for large-scale gene analysis that will integrate with
Alcohol, nicotine or illicit drug use affects many people. Over 20 years genes identified in the mouse programme.
there has been little advance in the drug treatment for addiction, with
most new treatments addressing physical drug withdrawal rather than Aim
treating drug craving and relapse.The contribution of genetic influences
The aim of the Integrated Project is to discover:
to addiction liability has been recently recognised but the identification
new candidate genes that are involved in addiction using human and
of genetic risk factors and genes involved in the molecular basis of
mouse approaches;
addiction is a new major challenge for the post-genomic era.This project
new genetic mechanisms that are involved in addiction;
is a collaboration between basic science groups, one SME and a leading
biotechnology company devoted to human studies on the role of genes new molecular targets for the treatment of addiction.
in complex diseases. This public-private partnership brings together a The human studies in this project will be carried out by Decode
highly innovative genealogical-led human genetics approach and a team Genetics in Iceland, using a genealogical approach to gene isolation,
which is central to their success in mapping genes for complex
of researchers with Europes best genomic mouse models.The core of disorders. It is based on taking a list of patients with the phenotype
the research effort will be the identification of genes associated with broadly defined, in this case addiction and subtypes of addiction,
drug addiction using an unbiased genome-wide approach. The strong analysing it using the genealogy database to identify families, who will
subsequently be recruited for a genome-wide scan for linkage. The
environmental component in the etiology of drug addiction has
genealogical analysis of large cohorts not only detects how individuals
presented a particularly difficult problem for genetic studies of this brain segregate into large families but also provides information on the
disorder in the past.The groups of this consortium propose to meet relationship between phenotypes.
this difficult challenge by combining powerful animal genetics and gene The human genetic component of this project will be complemented
profiling strategies with a human genetic approach that is relatively by linkage studies in mice.This platform will generate a large cohort
of phenotypically well-characterised mice from specifically designed
resistant to environmental modifications of the drug addiction
genetic crosses for linkage analysis.This analysis will provide chromo-
phenotype. Genes identified in this project will help to elucidate somal loci and genes that contribute to drug vulnerability in animal
dysfunction of genetic pathways in the addicted brain and provide new models. Subsequent human association studies will then help to
targets for the development of novel therapies. determine if these genes also play a role in drug addiction in humans.
This project also brings together groups in Europe that have developed
gene knockout animals of both the opioid and dopamine systems in
Background the brain.These systems are considered to be key players involved in
This is a major focused collaboration between 12 partners across the mechanisms of addictive drugs and thus provide us with unique
Europe including one leading genetics company and an SME developed animal model to identify genes involved in addictive processes. This
from the research success of one of the academic groups in this project extends the use of genetic models to identify genes that
partnership.The groups are spread across seven EU countries,including contribute to all components of addictive behaviour and also to study
two recently incorporated countries (Hungary and Poland) and one the fundamental mechanistic basis of addiction. The key role of the
associated country (Iceland). It is an integrated multidisciplinary project opioid and dopamine systems in addiction enables us to use the
bringing together genome-wide gene identification studies in addicted knockout models to identify, using gene expression studies, potential
patients with genomic studies in the mouse, to identify common genes candidate genes for addiction. In addition we propose to develop site-
involved in addiction. The animal experiments bring together seven specific and inducible knockout animals, which will not only provide
leaders in genetic studies of addiction in Europe that have, and will unique animal models for refined identification of addiction genes, but
further develop, a unique collection of gene knockout animals that can will also provide further fundamental information on addiction
be used to understand common underlying genetic mechanisms that mechanisms.

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Expected results
Coordinator
The project will carry out genotyping and linkage analysis of familial
material to identify genes linked to addiction to individual substances, Prof. Kitchen, Ian
and to identify gender difference in gene specific linkage, as well as University of Surrey
identifying genetic links with specific psychiatric phenotypes. The School of Biomedical and Molecular Sciences
project will dissect out potential genes that confer susceptibility to
Guildford GU2 7XH, United Kingdom
addiction by identifying candidate genes from animal studies, and
identifying genotype-phenotype relationships for addiction. Phone: +44 1483 689734
Fax: +44 1483 576978
The project will identify genes induced by addictive substances by
expression profiling in wild-type and gene knockout mice, and by E-mail: i.kitchen@surrey.ac.uk
expression profiling in strains of mice with altered sensitivity to Project web-site: To be developed.
morphine or cannabionoids. The project will identify if anxiety or Key words: Addiction, genomics, drug abuse, gene
stress are associated with drug abuse preference by phenotyping and knockout, genealogy, alcoholism, opiates,
quantitative trait loci analysis, and by evaluation of candidate genes dopamine
for association with drug addiction in humans and animal models.
The project expects to create conditional knockout mice with deletions Partners
of either mu, D2 and proenkephalin genes and will verify the
Prof. Maldonado, Rafael
neurochemical disruption of these animals. In addition, the project will
University Pompeu Fabra,
develop site-specific knockout mice, to delete receptors and peptides
in specific addiction related brain areas, and to analyse behavioural and Laboratory of Neuropharmacology,
neurochemical responses of site-specific deletion. In addition,we expect Department of Experimental Sciences and Health,
to characterise the involvement of opioid, dopamine and cannabinoid Barcelona, Spain
receptors and opioid peptides in the addictive properties of nicotine Prof. Kieffer, Brigitte L
studying behavioural responses to nicotine in wild-type and knockout Institut de Gntique et de Biologie Molculaire
animals. Further, we expect to characterise the role of specific opioid, et Cellulaire
dopamine and cannabinoid genes in addictive neurochemistry by studying CNRS/INSERM/ULP
neurotransmitter release in the nucleus accumbens of gene knockout Illkirch, France
mice,studying G-protein receptor activation in gene knockout mice,and Dr Borrelli, Emiliana
by studying electrophysiological changes in gene knockout mice. Institut de Gntique et de Biologie Molculaire
et Cellulaire
Directeur de Recherche, INSERM
Potential applications Illkirch, France
The potential of a fuller understanding of the genomics of addiction Prof. Zimmer,Andreas
is two-fold. Firstly, the opportunity to develop diagnostic tests to Life & Brain GmbH
identify an individuals susceptibility to become addicted to drugs,gives Laboratory of Molecular Neurobiology
a chance to protect vulnerable individuals more effectively. Secondly, Bonn, Germany
new treatments for drug addiction which result from understanding Prof. Przewlocki, Ryszard
the genetics of addiction have the potential to reduce the economic Institute of Pharmacology Polish Academy of Sciences
cost of addiction,which impacts heavily on the sectors of health,work, Department of Molecular Neuropharmacology
social services and the judicial system. Krakow, Poland
The ultimate objective of this Integrated Project is to provide new Prof. Freund,Tams F
knowledge that can be used by the participants or by European Hungarian Academy of Sciences
pharmaceutical companies to develop new drugs for the treatment of Institute of Experimental Medicine
both drug craving and relapse, which are core features of addictive Budapest, Hungary
disorders, or for providing new drugs for treating physical dependence Dr Thorgeirsson,Thorgeir E
and withdrawal from drugs of addiction. The scientific knowledge Decode ehf,
gathered will allow the consortium to identify specific genetic alterations Reykjavik, Iceland
in addicted patients and to develop novel treatments tailored to the
modulation of addictive processes that are under genetic control.
In addition, the production of novel knockout strains of mice with Acronym: GENADDICT
site-specific and temporally regulated mutations represents a major Project number: LSHM-CT-2004-005166
technical advance in gene manipulation in animals. These models will EC contribution: 8 100 000
enrich the scientific community and provide new means to study the Instrument: Integrated Project
Duration: 60 months
roles of selected genes in not only addiction but also several other Starting date: 01/01/2005
disorders of mood and pathological pain states.

96
EUROSCA BRAIN, NEUROLOGICAL

AND PSYCHIATRIC
DISEASES
European Integrated Project on spinocerebellar ataxias

(EUROSCA): Pathogenesis, genetics, animal models
and therapy
Summary Deciphering these mechanisms will lead to the development of drugs
preventing protein aggregation, neuronal death and stopping or
Twenty two European groups from nine countries with an excellent delaying the progression of these diseases.
reputation of clinical, clinical-genetic and basic research on
spinocerebellar ataxias (SCA) will aim at developing a treatment Aim
for patients suffering from this rare neurodegenerative disease.To Due to the low prevalence of SCA and because of its broad genetic
reach this goal, an international standard on the clinical evaluation heterogeneity, it is difficult to collect large numbers of patients.
Therefore the characterisation of the underlying pathogenetic
in form of a Core Assessment Programme for Interventional
factors and the potential to initiate large therapeutic studies are
Therapies of SCA (CAPIT-SCA) will be developed.The generation limited.This project will implement a network structure spanning
of the worlds largest collection of information on SCA, the nine European countries to collect the worlds largest set of
genetically defined patients (European SCA registry = EUROSCA-
European SCA Registry (EUROSCA-R), will ensure standardised
R). We will characterise these patients based on a novel set of
data acquisition and facilitate continuous recruitment of SCA clinical data using clinical rating scales, structural imaging, and
patients throughout Europe. The potential to include all larger electrophysiology to generate the largest and best characterised
European SCA families into linkage analysis will lead to the SCA patient collection (Core Assessment Program for
Interventional Therapies = CAPIT-SCA). The advantage of having
identification of new SCA loci and to the cloning of novel ataxia SCA families linked to a specific chromosomal region for which the
genes. Genotype-phenotype correlations will follow. Such a genetic cause has not been defined yet (SCA11, SCA13, SCA14,
combined effort will offer a systematic large-scale search for genetic SCA21) will be further strengthened by providing additional families
for which genetic linkage is unknown. It is anticipated that some
modifier factors in SCA. EUROSCA will also implement strong
genes will be cloned by EUROSCA within the next years. For the
research projects to generate and characterise cellular and patients themselves an oriented information network (EUROSCA
transgenic models, which will allow a more defined study of the web portal) will be established allowing easier contact with
specialised clinics of neurology. The scientific research objectives
pathogenesis and will serve as a tool for first therapeutic studies.
will concentrate on the most frequent and important SCA subtypes
Five core facilities and training programmes will complement (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) to decipher the
research efforts and clinical work. pathogenesis of these diseases, to generate animal and cellular
models, and to develop therapeutic strategies.All research groups
will get major support by highly specialised core facilities to produce
Background poly- and monoclonal antibodies, to generate Drosophila models,
Spinocerebellar ataxias (SCAs) consist of a highly heterogeneous to perform complex proteome and transcriptome analyses and to
group of progressive movement disorders usually manifesting in the decipher interacting proteins.
third to fourth decade of life and commonly lead to death after a
long duration of suffering for more than 20 years. The disease is
inherited as an autosomal dominant trait. Since a cure is currently
not available, the development of drugs for SCA will have great
impact.The prevalence of SCA in Europe is not well known but is
assumed to be less than 1:10 000. The high clinical and genetic
heterogeneity is manifested by the description of 21 SCA associated
loci and there are several lines of evidence of further loci implicated.
For nine of the SCA subtypes the underlying mutations have been
defined and shown to be caused by a trinucleotide repeat expansion,
most of them within the coding region of the respective gene and
encoding a polyglutamine chain. Pathohistologically, intranuclear
inclusions are detected in the affected regions of the brain. However,
the pathomechanism(s) underlying neuronal cell death and the
region specificity of the neurodegeneration remain unknown.

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EUROSCA
consists of four sub-structures: Coordinator
(i) Generation of the world largest patient DNA registry Prof. Rie, Olaf
(EUROSCA-R), which will allow extraordinary opportunities Eberhard Karls-Universitaet Tuebingen
to map novel gene loci, to identify novel SCA genes (SCA4,
SCA11, SCA13, SCA14, and SCA21), and to study modifier Department of Medical Genetics
genes of the age at onset (in particular of SCA1, SCA2, and Calwerstrae 7
SCA3).
72076 Tuebingen, Germany
(ii) Development of the first Unified Ataxia Rating Scale (UARS),
which will be used to generate a Core Assessment Programme E-mail: olaf.riess@med.uni-tuebingen.de
for Interventional Therapies (CAPIT-SCA). CAPIT-SCA is Project web-site: http://www.eurosca.org/
important to measure disease progression in SCA, one of the
major steps to objectively allow differentiation of genetically Key words: brain research, degenerative disease, rare
different SCA subtypes at the clinical level and one prerequisite disease, neurodegeneration, spinocerebellar
to monitor efficacy in clinical studies. ataxia, trinucleotide repeat disorders
(iii) Pathogenesis of the most common SCA sub-forms (SCA1,

SCA2, SCA3, SCA7, SCA17).To resolve these questions cellular Partners
and mouse models for most of the SCAs have already been
Institute of Child Health London, University College,
generated (SCA1, SCA2, SCA3, SCA7); others are being
prepared (SCA17, and Drosophila models).These models will
be used in initial therapeutic studies. Klinik und Poliklinik fr Neurologie, Universittsklinikum,
Bonn, Germany
(iv) Research groups are strongly supported by five core facilities
to generate monoclonal and polyclonal antibodies, to generate Hpital de la Salptrire, Institut National de la Sant et de
Drosophila models, to analyse the transcriptome and the la Recherche Mdicale, Paris, France
proteome and to build networks of interacting proteins.
Department of Biochemistry & Genetics,Istituto Nazionale
Neurologico Carlo Besta, Milan, Italy
Expected results Cambridge Institute for Medical Research, University of
worlds largest DNA registry for SCA patients (EUROSCA-R); Cambridge, United Kingdom
core Assessment Program for Interventional Therapies (CAPIT- Department of Neurology, University Medical Center
SCA); Nijmegen,The Netherlands
new epidemiological data; Department of Neurology, Universit Libre de Bruxelles,
Belgium
risk prediction, modifier genes;
Department of Genetics, Institute of Psychiatry and
defining new gene loci, disease gene cloning;
Neurology,Warsaw, Poland
disease models for SCA1, 2, 3, 6, 7, and 17;
Department of Medical Genetics and Child Development,
defining the pathogenesis common to polyQ type SCA; University of Pcs, Hungary
development of five potential drugs and testing in animal models.

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Service of Neurology, Servio Cntabro de Salud, Santander,

Spain
Department of Molecular Pathogenesis, University of
London, Institute of Neurology, London, United Kingdom
Ruhr-University Bochum,Department of Neurology,St.Josef
Hospital, Bochum, Germany
Neurogen Frankfurt, Johann Wolfgang von Goethe
University, Frankfurt/Main, Germany
Institut fr Humangenetik, Universitt Lbeck, Germany
Institut Jacques Monod, Centre National de la Recherche
Scientifique Paris, France
Neuroproteomics, Max Delbrck Centrum for Molecular
Medicine, Berlin, Germany
Centre European de Recherche en Biologie et Medecine,
IGBMC Illkirch, France
Department of Crystallography, Birkbeck College,
University of London, United Kingdom
Molecular Structure Division,National Institute for Medical
Research, London, United Kingdom
Acronym: EUROSCA
Duration: 60 months

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BRAIN, NEUROLOGICAL NeuroNE

AND PSYCHIATRIC
DISEASES
Molecular mechanisms of neuronal degeneration: from

cell biology to the clinic
Summary
NeuroNE is Europes premier research network for the creation of novel
therapeutic approaches to neurodegenerative disease and
neurotrauma,which represent an urgent socio-economic and human
need.The NeuroNE consortium (22 academic groups,five SMEs and one
management partner in nine different countries) is taking a multi-
disciplinary (functional genomics and proteomics,physiology,chemistry,
clinical studies) and multi-faceted (disease mechanisms, biology of cell
death and survival,regeneration mechanisms,high-throughput screening,
gene- and cell-based therapies) approach to this problem. Among the
neurodegenerative diseases, the network focuses on Alzheimer's
disease (AD), Parkinson's disease (PD), Huntington's disease
(HD) and amyotrophic lateral sclerosis (ALS). Spinal cord injury
(SCI) will be the main model for neurotrauma.NeuroNE brings together
investigators from different backgrounds (basic scientists,active clinicians Predicted number of Europeans affected by Alzheimer's disease.
From Wancata et al., 2003
and therapeutically-oriented SMEs) to work at all levels on the target
diseases using the methods of post-genomic science, molecular and cell
biology, animal models, therapeutic strategies and clinical studies.
Professional project management provides efficient integration, Expected results
realisation of scientific objectives and knowledge management. The The mechanisms involved in any neurodegenerative disease, in
scientific infrastructure of the network includes shared NeuroNE-funded neurotrauma exhibit some unique properties and many shared elements.
core facilities in seven centres.The network has employed a team of A limited number of basic technologies need to be developed which will
have an impact in many of these conditions.However,to be competitive,
scientists based in the participating laboratories who will conduct individual research groups usually focus on one particular disease. One
research and form collaborations among the different participants.The major impact of NeuroNE will be to accelerate the pace of discoveries
network has a programme of scientific meetings that will consist of three in neurodegeneration and neurotrauma by pooling expertise and
resources, and focus on cross-disease and cross-discipline relations.
major international plenary meetings and ten scientific workshops on
Europe is currently home to some of the leading scientific groups
specific topics.To feed back the benefits of integration into EU society, worldwide in the field of neurodegenerative diseases and neurotrauma.
the network is working with patient organisations, identified associated The generation of a network including these groups will generate major
synergies, further enhancing the competitiveness of European science
research groups who will benefit immediately from our infrastructures,
and biotechnology in these areas, and feeding forward into the
and has opened network meetings to identified scientists from emerging development of new treatments by European pharmaceutical companies.
research centres.
Background
Aim In the field of damage and repair of the nervous system Europe possesses
Neurodegenerative diseases and neurotrauma represent one of the scientific groups at least equal to those in other parts of the world.
greatest clinical and societal challenges of the coming century. As the However their effectiveness is limited by fragmentation, lack of access
average age of our population increases,the numbers affected by these to research resources, lack of clinical testing tools, lack of integration of
diseases of the nervous system will mushroom. The NeuroNE effort between large, medium and small industrial companies and a
consortium is addressing this problem by designing a long-term fragmented intellectual property environment.The NeuroNE network
multidisciplinary approach based on recent progress in the field of brings together actors involved at all levels (from basic research to clinical
neuronal degeneration and death together with a range of cutting- studies and drug development) in studying many aspects of the problem
edge therapeutic strategies. (different diseases, different biological phenomena, different therapeutic

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BRAIN, NEUROLOGICAL
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strategies) in many countries. Together the members of the network

will form an enterprise, integrated from basic science to clinical science Coordinator
to industry. Effective treatments for most of the diseases targeted by
the network have yet to emerge. The NeuroNE network and its Prof. Fawcett, James
collaborators will accelerate the development of these treatments, UNICAM
which, because of the large number of patients affected by its target Cambridge Centre for Brain Repair
diseases, will be pharmaceuticals of great financial value. E.D. Building
Robinson Way
Cambridge CB2 2PY, United Kingdom
Potential applications Phone: + 44 1223 33 11 88
Fax: + 44 1223 33 11 74
The overall task of the network is to create within the European
E-mail: jf108@cam.ac.uk
Union the conditions for emergence of novel mechanism-based
Project web-site: http://neurone.nuxit.net/
therapeutic approaches to neurodegenerative disease and
Key words: neurodegenerative diseases, neurotrauma,
neurotrauma. The NeuroNE scientists are convinced that research translational research, network of excellence
on the basic mechanisms of these diseases will help to identify
pharmacological targets that will be required for the development of
effective drugs for the treatment and prevention of neurodegenerative Partners
diseases. The combination of clinical groups with academic School of Life Sciences, Institute of Neurosciences - LEN,
laboratories and biotech companies specialised in the field is unique Lausanne, Switzerland
on this scale in Europe, and can challenge the best elsewhere. It will Interdisciplinary Center for Neurosciences, Neurobiology,
form the basis for future translation of clinically relevant basic Universitt Heidelberg, Germany
research into the clinics. Because of the growing importance of these Center for Neurological Medicine, Neurology, University
diseases for our ageing populations, these advances will have a of Gttingen, Germany
substantial impact, both socially and economically. Division of Neurobiology, Lund, Sweden
FMI, Basel, Switzerland
Department of Pharmacological Sciences, University of
Milan, Italy
TECHNION, Rappaport Institute, Haifa, Israel
Department of Medical Research and ImaGene Program,
Service Hospitalier Frdric Joliot, Orsay, France
INSERM, IBDM, Marseille, France
Ludwig-Maximilians-University,Adolf-Butenandt-Institute,
Department of Biochemistry, Munich, Germany
Karolinska Institute, Department of Neuroscience, Division
of Molecular Neurobiology, Stockholm, Sweden
Department of Basic Neuroscience, Centre Medical
Paired helical filament
Universitaire, Geneva, Switzerland
extracted from an Max-Planck Institute of Neurobiology, Department of
Alzheimer's disease brain Molecular Neurobiology, Munich-Martinsried, Germany
immunolabelled with an Neurologische Klinik, Universitt Ulm, Germany
anti-tau antibody.With Department of Neurology, Institute of Psychiatry London,
the courtesy of Dr. Marias United Kingdom
Gracia Spillantini Department of Human Genetics, Catholic University of
Leuven, Belgium
National Center for Biotechnology, CNB-C.S.I.C., Madrid,
Spain
Brain Research Institute, University of Zurich, Switzerland
Rita Levi Montalcini Center for Brain Repair, Neuroscience
Department,Turin, Italy
IBDM, Campus de Luminy, Marseille, France
Venetian Institute for Molecular Medicine, Padova, Italy
TROPHOS SA, Marseille, France
Acronym: NeuroNE
XANTOS Biomedicine AG, Munich,Germany
Project number: LSHM-CT-2004-512039 GENETRIX, Madrid, Spain
EC contribution: 8 300 000 PHARMAXON, Marseille, France
Instrument: Network of Excellence MEMOREC Biotec GmbH, Cologne, Germany
Duration: 48 months
Starting date: 01/01/2005 Inserm Transfert, Paris, France

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BRAIN, NEUROLOGICAL BrainNetEurope II

AND PSYCHIATRIC
DISEASES
Network of European brain and tissue banks

for clinical and basic neuroscience
Summary
BrainNet Europe II is a network of 19
established brain banks across Europe.
Having established a network of ten brain
banks in preparation for BrainNet Europe
II we now aim to integrate new members,
to spread excellence in collecting human
high-quality post-mortem brain tissue and
to foster research in the cellular and
molecular basis of neurological and mental
disorders and diseases, gender aspects and
the ageing process.
The main objectives of BrainNet Europe II

are:
1) to acquire and distribute well-

characterised and high-quality tissues for
basic research in neuroscience;
Graphical presentation showing the interdependencies of the components of activities.WP, workpackage
2) to provide a basis and quality control
system for RTD projects dealing with clinical or epidemiological importance such as Alzheimer's,Parkinson's,motoneuron disease,prion
aspects of neurological and psychiatric diseases; diseases, multiple sclerosis, schizophrenia and affective disorders will
be the focus of the network. In addition we will contribute to research
3) to standardise and harmonise neuropathological diagnosis;
in rare diseases, a research branch which can only be worked on
4) to increase the awareness of standardised neuropathological and successfully on an international European context.
clinical diagnosis in neurology and psychiatry at a European level;
5) to develop gold standards for tissue handling, safety aspects, quality Background
control and ethics.These standards will be the basis for using human In an era of rapidly growing knowledge about the biochemistry of the
post-mortem brain tissue in new investigative techniques such as brain, increasing insights into the genetics of brain diseases and a
greater understanding of functional anatomy through various imaging
expression profiling and proteomics;
techniques, there is an increasing need for brain and tissue banking,
6) to contribute to training and exchange of neuroscientists; i.e.the collection of brain tissue from well-characterised and diagnosed
patients.The reasons for this need are evident.While we collect ever
7) to use modern means of information technology to exchange data more data and details about the biochemistry, molecular biology and
physiology of nerve cells in culture or even in functioning animal brains,
within the network, to spread excellence and to disseminate
while we can biochemically characterise the cell biological processes
information to the general public. involved in some of the notorious neurological and psychiatric
diseases, there is still no clear picture emerging that would explain
These objectives will be reached by establishing a rigorous decision-
the relation of single biochemical findings and the pathophysiology or
making and management system resting on the members of the Project clinical progression of human brain disease. Brain banking will not by
Coordination Committee and assisted by an SME accountant company. itself solve all these problems.However,together with modern clinical
techniques, including brain imaging on the one side and molecular
Diseases of high frequency and outstanding medical and social
biology, genetics and biochemistry on the other, brain banking is at

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the interface of clinical and basic research on the brain and may technology. Many of the fundamental aspects of brain banking such
therefore contribute to both. as Ethics in Brain Banking are in a state of permanent change as the
integration of European countries and culture progresses. These
As systematic investigations have shown, more than 20% of idiopathic
themes therefore are in need of continual updates.
Parkinson's disease cases or even more of the clinical diagnoses in
these diseases are in strong disaccord with post-mortem With the advent of novel molecular biological technologies such as mass
neuropathological diagnosis (Hughes et al.J Neurol Neurosurg Psychiatr, spectrometry, expression profiling, proteomics and (functional)
1992, 55:181).This is a serious problem of quality control in modern genomics and their simplified application in pathology and
medicine not restricted to Parkinson's disease. It is a particular neuropathology, it is now timely to harness these technologies for
problem in an era in which powerful therapeutic tools have become brain tissue research. This in turn requires that we set standards
available but autopsy rates and quality control are declining. concerning the quality of tissues to be used for the application of
certain technologies.
Establishing a network of brain banking will serve several purposes:
first, to improve diagnosis and quality in neurology and psychiatry and This consortium of brain banks in Europe assembles the critical mass
second,to give an impetus to brain research.The network will contain necessary to tackle brain banking in the post-genomic era. In
clinical data and will in the future incorporate genetic and imaging particular we will approach the following areas:
information. Future activities that go beyond our immediate plans will
1) managerial and ethical problems specific to brain banking. This
show how much BrainNet Europe II will eventually be able to
includes setting standards for safety in brain banking, agreeing on
contribute to clinical and basic brain research.
and using neuropathological criteria, performing technical and
Diagnostic criteria as well as tissue handling procedures and diagnostic quality control exercises.
preservation techniques are related to scientific progress and thus
2) Brain Bank specific methodological research. This entails setting
will change over time.It does not appear realistic to assume that once
standards for working with human brain tissue using modern
these procedural questions have found solutions they will be
technologies such as laser capture microscopy,mass spectrometry,
permanent.Yearly consensus conferences will be held to keep up with
expression profiling etc.Taken together this will be the basis for
scientific progress and to adjust criteria and procedures accordingly.
research into human brain diseases using various heuristic and
hypothesis-driven approaches.
Aim 3) spreading of excellence beyond the network by using conventional
Brain diseases such as Alzheimer's and Parkinson's disease and publication in the scientific literature, giving talks at international
psychiatric disorders such as schizophrenia and major depression are meetings in the neurosciences and using electronic media.
among the most devastating and most common illnesses in our
modern-day world.With increasing life expectancy the aging nervous Expected results
system and its diseases are looming large at the beginning of the new
millennium. Numerous local and multinational research projects in 1. SHORT-TERM OBJECTIVES AND ACHIEVEMENTS
clinical and theoretical neuroscience are under way to take on the
1) to generate and foster collaboration between different centres
challenge.Brain and tissue banks have been set up in many institutions
undertaking brain banking and associated research activities;
of member states of the European Union in order to support research
projects on the biology of brain disease.It appears,however,that these 2) to maximise access to a range of tissues from particular diseases,
efforts have long been disparate. Integration of European brain banks collected from a number of different centres under standard
has been begun in a collaboration of ten brain banks in the 5th conditions and with well documented clinical histories;
Framework Programme and is growing but needs further support.
3) to maximise access to sufficient numbers of control cases
The major objectives of this network of excellence are to bring these appropriate to the disease of study;
individual efforts together, to integrate new groups, to spread
4) to harmonise protocols for individual disease-directed research;
experience to other groups in order to maximise the benefits of
collaborative brain banking. Brain and tissue banking at a European 5) to develop methodologies which would have wide application in
scale is of particular importance to study genetic and environmental brain banking, e.g. optimisation of different methods of freezing
influences of common diseases, to make possible studies on rare tissue;
diseases and to guarantee reliable standardised morphological
6) to disseminate current skills in enlisting public support for, and
diagnosis of brain diseases all over Europe. The latter is an
interest in, brain banking as a means of studying brain diseases;
indispensable prerequisite for good therapeutic studies.
7) to use the Internet for exchange of information,for raising scientific
BrainNet Europe started as a collaboration of ten brain banks and
awareness regarding currently available tissue samples, for
has now been opened for the integration of new members.
refinement of current diagnostic criteria,for multi-centre validation
Fundamental work has been performed concerning ethical aspects,
of qualitative and quantitative research data, and for networked
diagnostic standards, tissue handling and sampling protocols, as well
training sessions;
as data storage and exchange using various tools of information

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Management structure of BNE II
8) to train young researchers in the use and application of human 7) to devise strategies which lessen the impact of different
nervous system tissues for research, by means of short-term legislative practices concerning autopsies in different European
visits to other centres, training fellowships, and workshops. countries;
2. LONG-TERM OBJECTIVES AND ACHIEVEMENTS 8) to consider alliances with pharmaceutical and technology
industries;
1) to seek new ways to support the neuroscience research
community, e.g. blood and DNA collections and the routine 9) to consider inclusion of data regarding primate and transgenic
inclusion of non-CNS tissue samples in the Bank; resources;
2) to invite other Brain Banks to join the network if it is successful, 10) participation in, and access to, a networked source of disease
while being mindful of the need to preserve the viability and and control tissues of high quality will both stimulate and
worth of the project; facilitate the scientific output from individual centres, which in
turn will help to secure ongoing funding for individual Brain
3) to encourage the development of a collaborative ethos among
Banks.
smaller Banks and tissue resources on a national basis;
4) to encourage good practice and reduce duplication between
Banks and tissue collections;
5) to ensure that additional nervous system diseases of high
morbidity and burden on healthcare resources are addressed
within the network;
6) to ensure that high-quality samples are collected from rare
diseases and from foetuses in order to encourage and facilitate
research in ontogeny and unusual neuropathological material;

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Coordinator Universit di Bologna Dipartimento di Scienze

Neurologiche, Bologna, Italy
Prof. Kretzschmar, Hans
Department of Neuropathology, National Institute of
Ludwig Maximilians Universitaet Muenchen Psychiatry and Neurology, Budapest, Hungary
Institute of Neuropathology and Prion Research Human Brain Tissue Bank, Department of Anatomy,
Semmelweis University, Budapest, Hungary
Feodor-Lynen-Str. 23
Department of Neuropathology, Bereich Humanmedizin
81377 Munich, Germany
Georg-August University Goettingen, Germany
Phone: + 49 89 2180 78000
Department of Psychiatry and Psychotherapy, Saarland
Fax: + 49 89 2180 78037 University, Germany
E-mail: Hans-Kretzschmar@inp.med.uni-muenchen.de Department of Neuroinflammation, Imperial College of
Science Technology and Medicine, London, United
Project web-site: www.brainnet-europe.org
Kingdom
Key words: brain bank, neuroscience, genomics, pro-
Laboratoire danatomie pathologique, Hospices Civils de
teomics
Lyon, Lyon, France
Clinical Neurochemistry Lab, Julius Maximilians
Partners University Wrzburg, Germany
Department of Neuroscience and Neurology, GABO Gesellschaft fr Ablauforganisation,
Neuropathology section, University of Kuopio, Finland Informationsverarbeitung und
Pathology (Neuropathology), School of Clinical and Kommunikationsorganisation mbH & Co. KG, Munich,
Molecular Medicine, University of Edinburgh, Germany
United Kingdom
Huddinge Brain Bank, Karolinska Institute, Geriatric
Department, Neurotec, Stockholm, Sweden Acronym: BrainNetEurope II
Institute of Neurology, University of Vienna, Austria EC contribution: 7 740 000
Instrument: Network of Excellence
Division of Neuropathology and Neurology 5, Istituto Duration: 60 months
Nazionale Neurologico Carlo Besta, Milan, Italy Starting date: 01/07/2004
Institute Neuropathology, Hospital de Bellvitge,

Universitat de Barcelona, Spain
Laboratoire de Neuropathologie Raymond Escourolle,
Institut National de la Sant et de la Recherche Medicale,
Paris, France
Department of Neuropathology, King`s College London,
United Kingdom
Netherlands Brain Bank Foundation, Amsterdam,The
Netherlands
Department of Pathology / School of Medicine, National
and Kapodistrian University of Athens, Greece

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BRAIN, NEUROLOGICAL AUTISM MOLGEN

AND PSYCHIATRIC
DISEASES
Using European and International populations to identify

autism susceptibility loci

The Autism STREP group will pool data from 425 previously 1. Identification of top 6 linkage regions in combined multiplex sampl
and analysis of parent of origin and methylation effects in candidate
ascertained multiplex families and perform a meta-analysis to identify genes
the top 6 susceptibility regions.The top susceptibility regions will then
2. Identification of extended haplotypes for the top 6 regions in
be tested in genetically isolated populations of Finnish and Friesland Finnish and Netherlands singleton trios.
singleton trios to search for extended haplotypes that may further
3. Identification of any mutations/aetiological variants in brain
refine the critical regions. Brain expressed candidate genes in these expressed candidate genes in top 6 linkage regions.
narrowed regions will be tested for mutations and association with 4. Identification of any mutations/associations in named candidate
autism. In parallel, previously identified potential candidate genes will genes.
be tested for mutations/association in the combined sample of
multiplex families.
Background
Autism spectrum disorders are handicapping, neurodevelopmental
diseases of childhood that persist into adult life and which usually arise
on the basis of a complex genetic predisposition.The brain basis of
autism remains contentious, although post mortem studies provide
clear evidence of neuropathology with a prenatal onset. Identifying
susceptibility alleles is a key for understanding the molecular and
cellular nature of the brain dysfunction and for developing rational
preventative and treatment strategies to improve quality of life.
Although there has been significant progress towards identifying
susceptibility alleles,this has not yet been achieved by research groups
working independently.
Aim
1.To perform a meta-analysis of linkage in all multiplex families and
search for extended haplotypes in two isolated populations.
2.To test brain expressed candidate genes in 6 regions of linkage for
mutation and association with autism.
3.To test named candidate genes for mutations/association with
autism in multiplex families.
4.To assess and genotype new multiplex and singleton families.

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AND PSYCHIATRIC
DISEASES
Coordinator Prof.Agatino Battaglia

Prof.Anthony James Bailey Stella Maris Clinical Research Institute for Child &
The Chancellor, Masters and Scholars of the University of Adolescent Neuropsychiatry
Oxford Calambrone, Italy
University Section of Child and Adolescent Psychiatry Park Dr. Maretha de Jorge
Hospital for Children University Medical Center
Old Road, Headington Department of Chile and Adolescent Psychiatry
OX3 7LQ Oxford, United Kingdom
Phone: +44 1865 226517
Prof. Rudolf Minderaa
Fax: +44 1865 762358
Stichting Universitaire en Algement Kinder- en
Anthony.bailey@psych.ox.ac.uk Jeugdpsychiatrie Noord-Nederland
Project web-site: not yet established Faculty of Medical Sciences, Groningen University
Key words: Autism, Neurology, genetics, rare disease Department Child and Adolescent Psychiatry
Partners Prof. Christopher Gillberg
Prof. Patrick Farrar Bolton Goteborg University
Kings College London Department of Child and Adolescent Psychiatry
Child Psychiatry & MRC Centre for Social, Developmental & Gteborg, Sweden
Genetic Psychiatry
Dr. Irma Jrvel
Helsinki University Central Hospital
Prof.Ann Simone Le Couteur
Laboratory of Molecular Genetics
The University of Newcastle
Helsinki, Finland
Child and Adolescent Psychiatry/Mental Health School of
Dr.Thomas Bourgeron
Clinical Sciences
Institut Pasteur
Newcastle upon Tyne, United Kindgom
Groupe a 5 ans, Human Genetics and Cognitive Functions
Dr. Lennart Pedersen
Paris, France
Center for Autisme
Prof.Annemarie Poustka
Bagsvaerd, Denmark
Deutsches Krebsforschungszentrum
Prof. Marion Leboyer
Molecular Genome Analysis
Institut National de la Sant et de la Recherche Mdicale
Heidelberg, Germany
INSERM U513
Prof. Elena Maestrini
Creteil, France
Alma Mater Studiorum - Universit di Bologna
Prof. Bernadette Roge
Dipartimento di Biologa Evoluzionistica Sperimentale
Universit de Toulouse Le Mirail
Bologna, Italy
Centre d'Etudes et de Recherches en Psychopathologie
(CERPP)
Toulouse, France
Prof. Fritz Poustka Acronym: Autism Molgen
Johann Wolfgang Goethe-Universittsklinikum If not, proposal number: 512158
Klinik fr Psychiatrie und Psychotherapie des Kindes- und EC contribution: 2 000 000
Jugendalters Instrument: Specific Targeted Research Project
Duration: 36 months
Frankfurt, Germany Starting date: tbd
Prof. John Tsiantis
Natinoal and Kapodistrian University of Athens
Department of Child Psychiatry,Athens University Medical
School,Agia Sofia Children's Hospital
Athens, Greece

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BRAIN, NEUROLOGICAL SYNSCAFF

AND PSYCHIATRIC
DISEASES
Synaptic scaffolding proteins orchestrating cortical

synapse organisation during development
Summary Background
The development of neural circuitry is a vastly complex process, It is still unclear how the complex and finely tuned network of
protein-protein interactions defining both the presynaptic
and the role of many of its components - notably the control of cytomatrix and the postsynaptic compartment of cortical synapses
neuronal morphology, the formation of specific synaptic connections are regulated during development. It is well known that
as well as the localisation of key synaptic proteins - is still very poorly development of CNS synapses in vivo follows a stereotyped pattern.
Thus, during development - as well as during synaptic activity - a
understood. In this frame the present project aims to reach a more
profound rearrangement in synaptic protein composition and
comprehensive understanding of cortical networking during distribution occurs. These changes induce functional and
development, in particular of genes and their products governing morphological modifications allowing a reset of neuron activity in
order to better respond to a new environment. Such a modification
complex molecular mechanisms driving synaptic structuring and
represents the basis of structural dynamics of synapse, a process
organisation during development of cortical networks and that has a crucial role in development of the neuron system.
circuitries.
Several of these changes occur at the synaptic,cytoskeletal and scaffold
This project integrates the information about the role of different proteins level that represents a large proportion of the entire neuron
proteoma. In fact chemical synapses are characterised by electron-
candidate genes/proteins in synaptic formation,remodelling and function dense cytomatrices on both sides of the synaptic junction. On the
and it capitalises on results obtained in in vitro systems and translates pre-synaptic side dense projection or cytomatrix assembled at the
them to clinical application. The final aim is to identify key steps active zone (CAZ) defines the site of neurotransmitter release and
it is thought to organise membrane trafficking events underlying the
responsible for defect of development associated to mental
synaptic vesicle cycle. On the post-synaptic side the post-synaptic
retardation.Since intellectual performances are directly related to brain density (PSD) defines the neurotransmitter reception apparatus and
development and plasticity of excitatory synapses and these are is believed to anchor and cluster neurotransmitter receptors, ion
channels, and cell adhesion molecules and to connect them to the
generally located in cortical neurons, the project focuses primarily on
these structures.
The proteins identified as important factors in

the development of functional synapses are
then studied for their implications in the
development of synaptic dysfunctions using
different animal genetic models of mental
retardation.
Thus the project:
i) characterises gene products responsible for

synapse formation and function
ii) assesses the role of mutation/deletion of

selected genes in synaptic function in in vitro
systems and in intact organisms
iii) analyses the impact of mutations of

scaffolds in driving mental retardation.

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BRAIN, NEUROLOGICAL
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DISEASES
subsynaptic cytoskeleton and to elements of the postsynaptic signal Expected results

transduction machinery.
The development of neural circuitry is a vastly complex process,
In particular the identifications of scaffolding proteins as essential
and the role of many of its components - notably those that control
components of CAZ and PSD structure, has revealed new insights
neuronal morphology, formation of specific synaptic connections
into the molecular and assembly mechanisms of the synaptic
as well as the localisation of key synaptic proteins - are far from
apparatus.
being fully understood, although an alteration of this structure
In many cases multiple protein-protein interaction among scaffolding dramatically compromises brain function.This project contributes
and other synaptic relevant proteins have been described,highlighting to expand the knowledge in synapse formation during development
their appropriateness in driving the assembly of the synapse during not only by identifying key genes involved in this project but also
development. providing a picture of the correct spatial localisation of these
proteins in the synaptic space, the latter being fundamental to
Nevertheless,the discrete/distinct mechanism by which these proteins
understand their unique and specific role. Thus specific expected
participate in the regulation of synaptic development and function
results will be:
remain largely unknown.
characterisation of gene products responsible for synapse
Disturbance of dendritic spine shape, synaptic function and
formation, and function focusing on:
organisation of scaffolding proteins and receptor may lead to abnormal
development of cortical circuitry. The functional outcome of these the molecular scaffold cytomatrix of cortical synapses, identifying
disturbances is read as a defect of plasticity of these structures,a defect interacting elements with already known components and
that may lead ultimately to mental retardation. analysing their function at molecular and cellular level;
the molecular scaffold organising the post-synaptic domains and
Aim their role in sorting, targeting and function of ionotropic and
metabotropic membrane receptors;
The major goal of the present project is to reach a better
understanding of cortical networking during development and in the intercellular processes dynamically regulating the assembly
particular of genes and their products governing the complex of synaptic elements and determining the functional properties
molecular mechanisms driving synaptic structuring and organisation of the newly formed spines, i.e. phosphorylation processes
during development of cortical networks and circuitries. mediated by different classes of kinases.
In fact although genomic studies strongly contributed to our Evaluation of the role of mutation/deletion of selected genes in
knowledge on genes responsible for cortical development synaptic function in in vitro systems and in intact organism.
(identifying more than 437 gene products in foetal human brain), Evaluation of the impact of mutations of scaffolds in driving mental
it is known that the development of neural circuitry is a vastly retardation.
complex process, and the role of many of its components - notably
the control of neuronal morphology, the formation of specific
synaptic connections as well as the localisation of key synaptic Potential applications
proteins - is still very poorly understood.
SYNSCAFF generates novel information on the mechanisms
This project integrates the information about the role of different underlying synapse formation during development with reflection
candidate genes/proteins in synaptic formation, remodelling and on the causes of mental retardation.This is a major contribution,
function and it capitalises on results obtained in in vitro systems as the biological mechanisms underlying mental retardation remain
and translate them to clinical application, with the final aim to obscure. This novel information is also used to devise new
identify key steps responsible for defect of development associated innovative diagnostic tools in order to allow for an early diagnosis
to mental retardation. Since intellectual performances are directly and possibly treatment of these diseases.
related to brain development and plasticity of excitatory synapses
In addition, in a larger scale, most of proteins responsible for the
and these are generally located in cortical neurons, the project
structural organisation of the synapse are involved not only in
focuses primarily on these structures.
developmental disorders but also in some aspects of synaptic loss
Thus, the hypothesis that genes involved in the dynamic in neurodegenerative disorders. Thus, results obtained in the
organisation of pre- and post-synaptic compartment - studied in consortium have a larger impact, being applicable to several fields.
detail by the consortium - may be responsible for some aspects of SYNSCAFF provides new molecular targets for treatment. This
brain dysfunction leading to mental retardation, are tested. secures transfer of results generated to compounds that would
have in the future an impact on the early diagnosis of mental
The final goal is thus to define the molecular portrait of the cortical
disorders.
synapse during development, the key localisation of gene products
within the synaptic structure, which will possibly lead to the
definition of key genes involved in mental retardation.

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Coordinator Muller, Dominique

Faculty of Medicine, Pharmacology (Department APSIC)
Di Luca, Monica
Centre Mdical Universitaire
University of Milan
Switzerland
Department of Pharmacological Sciences
Gundelfinger, Eckart D
via Balzaretti, 9
Leibniz Institut fr Neurobiologie
20133 Milan, Italy
Abteilung fr Neurochemie und Molekularbiologie
Phone: + 39 02 5031 8374
Magdeburg, Germany
Fax: + 39 02 2048 8250
Sala, Carlo
E-mail: monica.diluca@unimi.it
Consiglio Nazionale delle Ricerche
Project web-site: www.synscaff.org
Institute of Neuroscience
Key words: cortical development, scaffolding proteins,
presynaptic cytomatrix, postsynaptic density, Milan, Italy
glutamate receptors
Calabresi, Paolo
NeurosciTorVerRome - Dipartimento di Neuroscienze
Partners
Universit di Roma Tor Vergata
Mulle, Christophe
Rome, Italy
Univ Bordeaux 2 - CNRS UMR 5091
Blahos, Jaroslav
Inst Francois Magendie
Institute of Experimental Medicine
Bordeaux, France
Czech Academy of Science
Fagni, Laurent
Prague, Czech Republic
Laboratoire de Gnomique Fonctionnelle
Jebavy, Lukas
UPR CNRS 2580
BioTest s.r.o.
Montpelllier, France
Konarovice, Czech Republic
Debanne, Dominique
Finocchiaro, Carla
Institut National de la Sant Et de la Recherche Mdicale
CF Consulting SrL
INSERM U464 Ionic Channels
Milan, Italy
Marseille, France
Prof. Lscher, Christian
Departments de Pharmacologie et Physiologie Service de Acronym: SYNSCAFF
Neurologie EC contribution: 1 900 000
Clinic of Neurology (Department NEUCLID), Lab for Duration: 36 months
Addiction Science Starting date: 01/01/2005
Switzerland

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EUROHEAD BRAIN, NEUROLOGICAL

AND PSYCHIATRIC
DISEASES
Migraine genes and neurobiological pathways

Summary patients and experimental animal models. In addition, the
EUROHEAD Consortium wants to promote and disseminate the
Migraine is a common chronic pain syndrome for which effective and existing and newly acquired knowledge of the underlying clinical and
neurobiological science of migraine syndromes among clinicians,
well-tolerated prophylactic agents are much needed. Increased
scientists, patients and general public worldwide.
knowledge of migraine pathophysiology is a prerequisite. In
EUROHEAD the genetic and neurobiological basis of the initiation of
Expected results
migraine attacks, the aura, and migraine pain will be investigated. A
In the EUROHEAD project, a Centre of Excellence has been
second focus of the EUROHEAD Consortium is to promote and
established in which many of the expert groups on primary
disseminate knowledge on clinical and neurobiological science of headaches are involved. Among the expected results are the
migraine and other primary headache syndromes. identification and validation of (new) loci and gene variants for
migraine, the analysis of functional consequences of migraine-
associated gene variants and mutations in cellular and animal models,
Background the correlation of genotypic data with migraine-endophenotypes,
Migraine is characterised by recurrent attacks (lasting 1-3 days) of an evaluation of headache science in Europe, and importantly further
disabling headache,associated symptoms and,in one-third of patients, promotion and dissemination of knowledge and awareness in the
neurological aura symptoms.Over 12% (two-thirds of which is female) community on this serious disorder.
of the general population have migraine attacks regularly (median
18/year).WHO rates migraine in the highest class of most disabling Potential applications
chronic disorders. Migraine-related annual costs in the EU amount to
10 billion.Acute attack treatments are satisfactory in less than half EUROHEAD research will be important for a better understanding
of patients. Effective and well-tolerated prophylactic migraine agents of the pathophysiology of migraine and future drug development.
are needed.
Genetic factors are involved in the
mechanisms for the attack, aura and
pain. Rare familial and common
complex types of migraine might share
common genes and pathways.
Unravelling the genetic and
neurobiological basis of migraine by
identifying and validating migraine
genes and studying their functional
involvement with various techniques in
patients and experimental models will
increase our knowledge and
awareness of migraine as a serious
neurobiological disorder.
Aim
EUROHEAD aims to unravel the
genetic and neurobiological basis of
the migraine. To this extent,
EUROHEAD will identify and
validate migraine genes and study
their functional involvement with
state-of-the-art techniques in

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Dr. Casari, Giorgio

Coordinator
Fondazione Centro San Raffaele del Monte Tabor
Prof. Ferrari, Michel
Human Molecular Genetics Unit
Leiden University Medical Centre
Department of Neuroscience
Department of Neurology
Milan, Italy
Albinusdreef 2, NL
Prof. Diener, Hans-Christoph
2300 RC Leiden,The Netherlands
Universitt Duisburg Essen
Phone: +31 71 526 2895
Fax: +31 71 527 8253
Essen, Germany
E-mail: M.D.Ferrari@lumc.nl
Prof. Olesen, Jes
Project web-site: www.eurohead.org
Glostrup University Hospital
Key words: headache, migraine, pain, genetics,
neurobiology, man, transgenic mouse Danish Headache Center
models, response, treatment Dept. Neurology
Copenhagen, Denmark
Partners Prof. Schoenen, Jean
Prof. Palotie,Aarno
University of Lige
University of Helsinki
Department of Neuroanatomy & Neurobiology
Finnish Genome Center
Faculty of Medicine Headache Research Unit
Helsinki, Finland
Lige, Belgium
Prof. Goadsby, Peter
Prof. Nappi, Giuseppe
Institute of Neurology
IRCCS Neurological Institute "Casimiro Mondino"
University College London
Pavia, Italy
Headache Group
Acronym: EUROHEAD
Prof. Pietrobon, Daniela Project number: LSHM-CT-2004-504837
Universit degli Studi di Padova Instrument: Specific Targeted Research Project
Duration: 36 months
Dipartimento di Scienze Biomediche Sperimentali Starting date: 01/05/2004
Padova, Italy

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SPASTICMODELS BRAIN, NEUROLOGICAL

AND PSYCHIATRIC
DISEASES
Genetic models of chronic neuronal degeneration

causing hereditary spastic paraplegia
Summary
Neurodegenerative disorders,a heterogeneous
group of chronic progressive diseases, are
among the most puzzling and devastating
diseases in medicine. Indeed they are
Semithin section
characterised by onset in adult life, distinct
of the spinal cord
clinical phenotypes,and specific degeneration of of a 8 month-old
subsets of neurons and axons. Hereditary paraplegin-deficient
spastic paraplegia (HSP) is a disorder that results mouse showing
axonal swelling.
in progressive weakness and spasticity of the
lower limbs affecting approximately 1 in 10 000
individuals. Heterogeneity characterises HSP in
both clinical and genetic aspects.Little is known
about the pathogenesis of HSP and
consequently no specific treatment is available
to prevent, cure or delay progression of Background
symptoms of HSP. Electrophysiological and pathological findings point
Hereditary spastic paraplegia (HSP) consists of a heterogeneous
to the corticospinal tracts,dorsal columns and the spinocerebellar fibres group of neurodegenerative diseases characterised by progressive
as the structures primarily affected by HSP. lower-limb weakness and spasticity and subtle impairment of the
vibratory sense. Age of onset is quite variable, generally between
Two main pathogenetic hypotheses for the neurodegeneration seen in 10 and 40 years old. HSP has been classified traditionally as pure
HSP, as well as other neurodegenerative conditions, have recently or complicated, depending on whether spastic paraplegia is the
emerged, suggesting that impaired mitochondrial function and/or only symptom or whether it is found in association with other
neurological abnormalities, such as optic neuropathy, retinopathy,
defective subcellular transportation mechanics play a crucial role.In fact, extrapyramidal symptoms, dementia, ataxia, mental retardation and
HSP-causing mutations have been found in gene products involved in deafness.
mitochondrial function, such as paraplegin and HSP60, and axonal Neuropathological analyses of tissues from a small number of
trafficking, such as kinesin and, possibly, spastin and spartin. This individuals with pure HSP have shown axonal degeneration
consortium of European groups intends to provide a multi-faceted involving the more distal portions of the longest motor and
sensory axons of the central nervous system (i.e. the crossed and
comprehensive approach to study the pathogenesis of HSP with a uncrossed corticospinal tracts, the fasciculum gracilis and the
particular emphasis on the role of mitochondrial dysfunction and spinocerebellar tracts).A specific pattern of degeneration is seen
impaired axonal transport, through the production and extensive in HSP, during which the cell bodies remain largely intact while
the degeneration is principally limited to the cell axon and may
characterisation of seven novel mouse models for this disease,in parallel be a dying back axonopathy, beginning distally and proceeding
with the recently developed paraplegin null mutant. The proposed towards the cell body.
strategy is a highly integrated effort to study the function of several A more precise classification of HSP forms therefore originates from
HSP genes,with the final goal of identifying common mechanisms leading the inheritance pattern,which may be autosomal dominant,autosomal
to axonal degeneration, which will be potential targets of a therapeutic recessive or X-linked recessive.So far,21 loci have been mapped (listed
SPG1 to SPG21);however,causative mutations have been found in nine
intervention in the long term. genes only. Mutations in the cell adhesion module L1, L1CAM (SPG1)
and in the proteolipid protein, PLP (SPG2) cause X-linked forms of
HSP characterised by defects in the development of the corticospinal
tract and in axonal-glial interactions,respectively.Little is known about

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known autosomal HSP genes encoding spastin (SPG4), paraplegin mechanisms would result in a dying-back effect, typical of this late
(SPG7),atlastin (SPG6),spartin (SPG20),aspardin (SPG21),while Hsp60 progressive neurodegeneration.
is a well-characterised shock-response protein (SPG13) and the neural
A possible unifying alternative mechanism can be hypothesised:
specific kinesin gene KIF5A (SPG10) is a member of the kinesin
impaired mitochondrial function generates huge aberrant
superfamily of molecular motors that transport cargoes along
mitochondria, which engulf the peripheral cellular trafficking.
microtubules.
Atlastin is a novel GTPase that has sequence homology to members
of the dynamin family of large GTPases, particularly guanylate binding Aim
protein-1. Spartin is responsible for Troyer Syndrome, an autosomal Current therapies provide only symptomatic relief; none significantly
recessive HSP, and is homologous to proteins involved in endosome alter the course of disease.Therefore, there exists a major medical
morphology and protein trafficking of late endosomal component. need that demands the development of new and more informed
Aspardin is responsible for Mast syndrome (a spastic paraplegia, therapeutics for the efficacious treatment of neurodegenerative
autosomal recessive with dementia). Both spastin and paraplegin are diseases.While many diseases of the motor neurons have no known
AAA proteins, ATPases associated with different cellular activities. genetic component, recent investigations have begun to identify the
Members of this superfamily of ATPases exert chaperon-like activities causative genes for some familial forms. In turn, this leads to the
and mediate assembly and disassembly of macromolecular structures possibility of transgenic animal models of human disease, which in
involved in different cellular processes. previous studies have substantially contributed to the identification
Paraplegin resembled a family of mitochondrial metalloproteases of many promising new therapies. A major limitation to the study of
well-characterised in yeast and was shown to localise in the neurodegenerative disease is that the affected tissues are not
mitochondrion. Mutations in paraplegin cause neurodegeneration in accessible until after death, hampering studies of the early stages and
an autosomal recessive form of HSP, but the pathogenetic mechanism the progression of the pathological features. Animal models where
of this disorder, in particular the role of mitochondria, is presently the genes mutated in human HSP are modified are an important tool
not understood. to overcome this obstacle.
Observations of members of this Consortium (Partners 1 and 4)

show that paraplegin and the homologous protein AFG3L2 Expected results
constitute the m-AAA protease complex. Mitochondria of HSP
This consortium of European groups intends to provide a multi-
patient (SPG7) have indeed a functional deficit that could result from
faceted approach for the study of the HSPs and these mechanisms.
impaired protein quality control, causing an accumulation of
Although the molecular basis has been unravelled for several forms
misfolded proteins within the mitochondrial matrix. An additional
of HSP in the last few years, the mechanisms resulting in axonal
mitochondrial protein, Hsp60, has been found mutated in a form
degeneration in this disease are still largely unknown. However
of HSP. Hsp60 is a representative of the type I chaperonin subfamily
animal models offer an important tool to overcome this obstacle.
of molecular chaperones that are involved in folding of bacterial,
The objectives of this work package are: 1) the generation of mouse
mitochondrial and chloroplast proteins. Type I chaperonins are
models for different forms of HSP; 2) the phenotypic
highly conserved throughout evolution and play an important role
characterisation of these models according to common,
in quality control of proteins, which seems to be a preferential
standardised protocols.
mitochondrial target for SPG13 and SPG7.
Differently, some evidence from transfection
experiments show that spastin interacts with
microtubules and seems to modulate microtubule
dynamics, an essential attainment for maintenance of
long axons,beside a still unclear possible role at nuclear Electron micrograph
level. Only little is known, however, about the function of the spinal cord of
of this protein and its role in the pathology of HSP. a12-month-old para-
The specificity of the axonal damage in HSP plegin-deficient mice show-
apparently contrasts with the wide distribution and ing segmental swelling of a
range of functions carried out by the few gene longitudinally cut axon.
products known to cause the clinical phenotypes. Filamentous aggregates
However, we think to envisage two possible and and degenerating
pathogenetic mechanisms. The mitochondrial way mitochondria accumulate
seems to affect neuronal metabolism, in particular at in the axoplasm.
the axon extremity, by reducing the available energy.
On the other hand, the cellular trafficking impairment
would limit the turnover of fresh molecules and
organelles to and from the periphery of neurons. Both

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A critical component of the proposed project is the development

and characterisation of a number of mouse models of hereditary
spastic paraplegia, which include: spastin (SPG4), paraplegin (SPG7), Coordinator
Hsp60 (SPG13), spartin (SPG20), Afg3l1 and Afg3l2 and prohibitin.
This comprehensive range of models affords this project an Dr Casari, Georgio
invaluable resource for the study of disorders of the motor neuron, San Raffaele Scientific Institute
in particular the hereditary spastic paraplegias. We will use this DiBit
resource, in parallel with a range of cell models and other studies,
to examine two hypotheses for motor neuron degeneration: Via Olgetttina, 58
defective mitochondrial function, and abnormal subcellular 20132 Milan, Italy
transportation mechanics.
Phone: + 39 02 2643 3502
Fax: + 39 02 2643 4767
E-mail: casari.giorgio@hsr.it
Project web-site: http://www.spasticmodels.org/
(under construction).
Key words: hereditary spastic paraplegia, paraplegin,
spastin, spartin, HSP60, motoneuron, mouse
models.
Partners
Dr Rugarli, Elena
TIGEM
Naples, Italy
Prof. Langer,Thomas
Universitt zu Kln
Institut fr Genetik,
Cologne, Germany
Prof. Bross, Peter
Aarhus University Hospital Skejby Sygehus
Brendstrupgaardsvej
rhus N, Denmark
Dr Crosby, Andrew
St. Georges Hospital Medical School
Prof. Deufel,Thomas
Instituts fr Klinische Chemie und
Laboratoriumsdiagnostik
Universittsklinikum Jena
Jena, Germany
Acronym: SPASTICMODELS
Duration: 36 months

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BRAIN, NEUROLOGICAL NCL-models

AND PSYCHIATRIC
DISEASES
Dissecting neuronal degeneration:

Neuronal ceroid lipofuscinoses from genes to function
Summary 3) to further characterise the neuronal phenotype of the five existing
mouse models and to develop one novel mouse model of NCL;
The aim of the NCL-models project is to reveal pathogenetic 4) to define the mechanisms and selectivity of neurodegeneration in
mechanisms in neuronal ceroid lipofuscinoses.Our goal is to carefully the model organisms;
characterise the individual NCL proteins to further understanding of 5) to develop and use bioinformatic tools for efficient analysis of
their normal roles and the molecular mechanisms by which loss of the metabolic pathways involved in neuronal degeneration;
their function leads to neurodegeneration. The data we obtain will 6) to organise effective European research training in the functional
also have significant implications for other disorders,providing insights genomics of neurodegeneration;
into the cellular processes that influence neuronal death and ageing. 7) to integrate the complex data arising from different model
The project uses a multidisciplinary approach, in which a key element systems in order to understand the cellular pathogenesis unique
to each NCL or in common between the NCLs thereby
is the generation of novel models for NCL.These models, including providing the knowledge base for future drug development.
cell, yeast, nematode and mouse models will then be used to study Additionally, actions to raise public participation and awareness
the pathogenetic mechanisms of NCLs by a variety of techniques will be taken.
including molecular genetics, cell biology, mRNA and protein
expression profiling, proteomics, and morphological approaches.The Expected results
combination of top-level European NCL scientists will facilitate the The present project will significantly add to our knowledge of the
integration of research capacities across Europe,increasing coherence function of the NCL proteins, the mechanisms of neurodegeneration
and the disturbed metabolic pathways underlying each form of NCL.
and providing critical mass of investigators. The integrated This project will lead to better understanding of the maintenance of
multidisciplinary research enables direct interactions between the nervous system,and will provide the knowledge base for designing
technology and biology and will provide the knowledge base essential therapy, and essential tools for evaluating subsequent therapeutic
approaches.
for the rational design of therapeutic interventions.
Research training is an extremely important part of this
multidisciplinary programme and one central task is to organise and
Background monitor the research training of young scientists devoted to functional
The neuronal ceroid-lipofuscinoses (NCLs) are collectively the most genomics and neurobiology. Exchange of these junior investigators
common inherited progressive encephalopathy of childhood.Each form between laboratories will help to provide them a thorough training
of NCL is characterised by the progressive death of cortical neurons in different techniques. It is also expected that exchange of young
and these rare diseases provide an excellent model to define the scientists between laboratories of the collaborative network will
molecular events that result in neurodegeneration. Using genomic facilitate the achievement of the research goals of the NCL-models
approaches we have identified six genes mutated in different forms of project.
NCL: PPT1, CLN3, CLN5, CLN6, CLN8, and cathepsin D. Deficiencies
in these proteins result in a group of fatal disorders with clinical Potential applications
presentation that ranges from infantile lethality to later onset and more
protracted forms. Despite the identification of these proteins, the The ultimate impact of the proposal is in providing the basis for
underlying pathogenetic mechanisms remain unclear. therapeutic approaches for these progressive, fatal
neurodegenerative disorders of childhood.The entire NCL-models
network aims at improving the health of NCL patients and quality
Aim of life for families affected by this major paediatric neurodegenerative
The project has been divided into seven specific objectives: disease.The economic development and impact produced by these
research achievements will be assessed during the course of the
1) to analyse the localisation, transport and molecular interactions project. Once these research data influence, initiate or enhance
of the individual NCL proteins in neuronal and non-neuronal cell therapeutic activities and form the basis of clinical trials, economic
models; benefits will be expected not only for the manufacturers of eventual
2) to generate and analyse yeast and nematode models for different therapeutic regimens but also via lowering disease costs incurred
forms of NCL; by NCL patients and their families.

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Coordinator Dr Lehesjoki, Anna-Elina

Dr Jalanko, Anu Neuroscience Center
National Public Health Institute, Department of Molecular Department of Medical Genetics and Folkhlsan Institute
Medicine, Biomedicum Helsinki of Genetics
P.O. Box 104 Biomedicum Helsinki
00251 Helsinki, Finland University of Helsinki, Finland
Phone: + 358 9 4744 8392 Dr Tyynel, Jaana
Fax: + 358 9 4744 8480 Institute of Biomedicine/biochemistry
E-mail:Anu.Jalanko@ktl.fi University of Helsinki, Finland
Project web-site: www.nclmodels.org Dr Cooper, Jon D
Key words: neurological disorder, neurodegeneration, Pediatric Storage Disorders Lab
neuronal death Department of Neuroscience
Institute of Psychiatry
Partners King's College London
Dr Peltonen-Palotie, Leena London, United Kingdom
Department of Medical Genetics Dr Taschner, Peter
University of Helsinki and Department of Molecular Department of Human Genetics
Medicine Sylvius Laboratories
National Public Health Institute Biomedicum Leiden,The Netherlands
Helsinki, Finland Dr Braulke,Thomas
Dr Mole, Sara E University Hospital Hamburg-Eppendorf
Department of Paediatrics and Child Health Hamburg, Germany
Royal Free and University College Medical School
University College London, Bloomsbury Campus
Acronym: NCL-models
London, United Kingdom Project number: LSHM-CT-2003-503051
Dr Mitchison, Hannah EC contribution: 2 000 000
Senior Lecturer in Molecular Genetics Duration: 36 months
Department of Paediatrics and Child Health Starting date:01/01/2004
Royal Free and University College Medical School

University College London,

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BRAIN, NEUROLOGICAL NEUROKCNQPATHIES

AND PSYCHIATRIC
DISEASES
Cell biology of rare monogenic neurological

KCNQ disorders
Summary The M-current is a target of acetylcholine and it is thought to play
a role in learning and memory, and in epilepsy. Indeed, KCNQ
Mutations in three KCNQ genes are associated with rare monogenic channel modulators may have therapeutic potential in the
treatment of epilepsy, neuropathic pain and neurodegeneration. For
neurological disorders prompting us to study the cell biology underlying
this reason, we must understand more precisely how these
these disorders, and to identify the processes that control KCNQ modulators of KCNQ channels work to fully explore this
channel function. The biochemical and biophysical affects of these therapeutic potential.
mutations in the channels,their modulation by second messengers,and Finally, KCNQ channelopathies provide an example of the
the physiological significance of protein-protein interactions will be importance of gene dosage in inherited diseases. Thus, mutations
that only moderately reduce the expression of a KCNQ gene could
addressed. Because some mutations in the KCNQ loci do not appear
cause neurological disorders and mutations responsible for
to lie in the coding region, we will study the transcriptional control of producing a disease may lie outside the coding region.
these genes. Furthermore, mouse models will be produced to gain a
more precise idea of the pathology of these diseases. Finally, the Aim
molecular basis for drug specificity will be analysed to define the mode
The principal aim of this project is to determine the role of M-
of action as well as to identify and characterise new drugs that affect channels in neuronal and non-neuronal physiology, and to
the function of these channels. understand the cellular basis of rare neurological syndromes
associated with KCNQ channel dysfunction. The function and
potential role of KCNQ5 in disease will also be assessed in mutant
Background mice. Conditional KCNQ knock-out mice will aid in further
Of the rare monogenic neurological disorders caused by mutations elucidating the involvement of the M-current in neuronal plasticity
in KCNQ potassium channels, neonatal convulsions (BFNC), a rare and we shall also analyse the role of KCNQ channels in human
autosomal-dominant disorder, are caused by mutations in KCNQ2 deafness in greater depth. We aim to understand the processes
and KCNQ3, whereas in KCNQ4 they cause progressive hearing underlying cellular targeting and trafficking of the channels and to
loss.These genes are responsible for the M-current and KCNQ4 identify targeting signals within the channel.We will study the role
may contribute to the short electrical time constants needed in of associated proteins and second messenger systems in regulating
neurons of the auditory pathway. Since KCNQ5 can also M-channel function as well as the interactions between such
contribute to this current, it too may provoke neurological elements, and we will identify and study the role of the KCNQ
disorders. ligands in channel function. We also plan to study how the
expression of these genes is regulated. Finally, the role of M-
The intracellular C-terminal domain of KCNQ mediates channels in neuropathic pain processing warrants deeper
interactions with other subunits and proteins. This region is also investigation and we plan to identify the molecular determinants
important for efficient surface expression selective retention, for the pharmaceutical regulation of these channels, which may help
endocytosis and intracellular trafficking, as well as the subcellular in developing more selective drugs
localisation of KCNQ channels. However, although proteins that
interact with KCNQ subunits have been identified, the signals
controlling these processes remain unknown. Similarly, the Expected results
regulation of the M-current by neurotransmitters is poorly We expect to gain a much better understanding of the cell biology
understood and the intracellular second messengers involved of these channels and the way in which disease-causing mutations
remain elusive. Nevertheless, information is available regarding the affect these processes. Furthermore, light will be shed on how the
influence of phospholipase C (PLC), PKC activation, the release of behaviour of these channels is modulated by associated proteins,
internal calcium, PIP2 and CaM binding on the function of M- neurotransmitters and second messenger systems, as well as the
channels.To help us clarify the mechanisms by which the cell biology interactions that occur between these elements. We expect to
of these channels is controlled and how it may be affected in human obtain important insights into the role of KCNQ channels in
disease, it is clear that we must study the relationships between different human conditions, creating the basis for novel therapies.
these regulatory proteins.

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This aspect will be enhanced by augmenting our understanding of

the action of drugs that alter the activity of these channels. Finally,
we hope to advance both our understanding of the transcriptional
control of the genes encoding these proteins. Coordinator
Dr Villarroel, Alvaro
Potential applications Consejo Superior de Investigaciones Cientficas
The potential applications that might arise from this project involve Unidad de Biofisica CSIC-UPV/EHU
the possible therapeutic benefits of treating the diseases that arise
Universidad del Pas Vasco
due to mutations in these genes as well as in neuropathic pain.
Furthermore, it is likely that the insights into the way that these Barrio Sarriena S/N
channels are modulated will also be applicable to other diseases
48940 Leioa (Bilbao), Spain.
caused by similar proteins, within and outside the nervous system,
as well as to diseases involving other types of proteins. Phone: + 34 94 601 3225
Fax number: + 34 94 601 3360
E-mail: gbxvimua@lg.ehu.es
Project web-site: www.KCNQ.com
Key words: neurobiology, cell biology, rare diseases,
monogenic, ion channels, mouse models,
KCNQ, Kv7, potassium channels, struc-
ture/function, gene expression, protein
interactions, cell physiology, electrophysi-
ology
Partners
Centre for Molecular Neurobiology, Hamburg University,
Germany
Department of Physiology, University College London,
United Kingdom
Department of Physiology, Institute of Basal Medical
Sciences, Medical Faculty, University of Oslo, Norway
NeuroSearch A/S, Ballerup, Denmark
Unit de Gntique des Dficits Sensoriels, INSERM
U587, Institut Pasteur, France.
Department of Neuroscience, Section of Pharmacology,
University of Naples Federico II, Italy
School of Biochemistry & Molecular Biology, University
of Leeds, United Kingdom.
Acronym: NEUROKCNQPATHIES
Duration: 36 months

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AND PSYCHIATRIC
DISEASES
X-linked Adrenoleukodystrophy (X-ALD): pathogenesis,

animal models and therapy
Summary biochemically characterised by the accumulation of fatty acids with
more than 22 carbon atoms (very-long-chain fatty acids;VLCFA); but
Our ultimate goal is to develop new therapies for X-linked adreno- the role of VLCFA accumulation in the pathophysiology of the disease
remains unknown.The gene affected in X-ALD codes for a protein
leukodystrophy (X-ALD), the most frequent inherited monogenic
that is probably involved in the transport of VLCFA into a specific
demyelinating disease of the central nervous system (1:18,000). X- intracellular organelle, called the peroxisome.The ALD protein is an
ALD is characterised by extensive phenotypic variability, which is ABC (ATP-binding-cassette) half-transporter, which forms either
homo- or heterodimers with two other homologous peroxisomal
not correlated to ALD genotype, and leads to death in boys due to
ABC half-transporters,the ALD-related protein and PMP70.Like many
cerebral demyelination and to motor disability in adults due to spinal other ABC transporters, the ALD protein binds and hydrolyses ATP
cord degeneration. Allogenic bone marrow transplantation, proven to become functional. VLCFA are considered good candidate
substrates for transport across the peroxisomal membrane by the
to be beneficial in X-ALD, can be applied only to a limited number
ALD protein,but proof of such transport has yet to be demonstrated.
of X-ALD patients.Thus, there is no treatment for the majority of In addition,different combinations of heterodimers may have different
patients, in particular those with the severe cerebral form of X-ALD substrate specificity.
and adults with adrenomyeloneuropathy (AMN). Understanding of Although being a monogenic disorder, X-ALD shows a wide
the pathogenesis is necessary for the development of novel phenotypic variation even within families. There is no correlation
between the phenotype and the type of ALD gene mutation or the
therapeutic strategies.The still unresolved transporter function of
levels of VLCFA in fibroblasts or plasma of X-ALD patients. This
the ALD protein will be studied in reconstituted liposomes.To get phenotypic variability ranges from severe cerebral forms that lead to
further insight into the pathogenesis of X-ALD, we aim to identify death in 5 to12-year-old boys to mild paraparesis (adrenomyelo-
genes and proteins that are differentially regulated in the target neuropathy, AMN) in adults at 25-50 years of age. The lack of any
genetic or biochemical tools to predict the phenotype of X-ALD
tissues of patients with cerebral ALD and AMN using Affymetrix hinders the development of preventive or therapeutic approaches.
analysis of differential mRNA expression and a proteomics approach Among the neurometabolic diseases, X-ALD is unique by the
based on MALDI-TOF mass spectrometry. Additional approaches occurrence of a striking brain inflammatory response that resembles,
but is distinct from, that observed in multiple sclerosis. This
such as mapping of quantitative trait loci will be applied to identify immunological response is the main neuropathological factor that
modifier genes that may contribute to the phenotypic variability of seems to differentiate the severe cerebral forms of X-ALD from AMN.
X-ALD.We will generate new mouse models that represent a wider There are some speculations in the literature about how this
inflammatory response may lead to the death of oligodendrocytes,
phenotypic spectrum of the disease for a more efficient evaluation
but its trigger and mechanism are unknown. Since X-ALD is
of therapeutic strategies. Furthermore, we will evaluate four considered a genetic disease with loss-of-function and in the absence
promising new therapy strategies: ALD gene transfer into of data suggesting that VLCFA are metabolised differently in humans
and in rodents, it seemed probable that complete inactivation of the
haematopoietic stem cells, into mesenchymal stem cells, and by
Ald gene in mice would mimic the clinical symptoms observed in X-
direct injection of viral vectors, and pharmacological induction of a ALD patients. The Ald-deficient mice develop a neuropathological
related gene as a substitute for the deficient ALD gene. Only the phenotype late in life that resembles AMN, but no cerebral
demyelination.It is hypothesised that the expression of modifier genes
joint effort of the highly qualified partners of this proposal will allow
and/or epigenetic factors contributes to the susceptibility or
achieving our ambitious aims. resistance to develop cerebral demyelination both in X-ALD patients
and Ald-deficient mice.The only therapeutic approach proven to be
Background beneficial in X-ALD is allogenic bone marrow transplantation (BMT).
BMT can reverse or stabilise cerebral demyelination when the
X-ALD is the most common (1:18 000) genetic disorder affecting the procedure is performed in boys at an early stage. However, this
myelin within the central nervous system (CNS). It affects boys procedure is associated with a significant mortality risk (10-25%) and
(between 5-12 years), adult males (20-50 years), and women (> 40 can only be offered to a limited number of X-ALD patients.Thus,there
years).All forms of X-ALD are characterised by severe neurological is no treatment for the majority of X-ALD patients,in particular those
abnormalities frequently resulting in early death. X-ALD is with the severe cerebral form of X-ALD or adults with AMN.

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Aim
a) to identify the natural substrates for the ALD protein and other related Coordinator
peroxisomal ABC half- transporters (ALD-related protein and PMP70) Prof. Berger, Johannes
whose overexpression, at least partially, overcomes the biochemical
Medical University of Vienna
defect observed in X-ALD cells;
Center for Brain Research
b) to resolve the role of VLCFA in the pathogenesis of X-ALD; Division of Neuroimmunology
c) to get insight into the pathogenesis of X-ALD,we aim to identify genes Spitalgasse 4
and proteins that are differentially regulated in the brain of patients 1090 Vienna, Austria
with childhood cerebral ALD and AMN; Phone: + 43 1 4277 62812
d) identification of the modifier genes that may contribute to the Fax: + 43 1 4277 9628
phenotypic variability of X-ALD; E-mail: johannes.berger@meduniwien.ac.at
e) to characterise in detail the neurodegenerative features of the existing Key words: degenerative diseases, gene therapy,
mouse models of X-ALD and to generate new models that represent genomics
a wider phenotypic spectrum of the disease;
f) to establish a new generation of lentiviral and AAV vectors for gene Partners
therapy and to test the efficacy of gene therapy approaches in mouse Prof. Aubourg, Patrick
models aiming at targeting the ALD gene ex vivo in haematopoietic Institut National de la Sant et de la Recherche Medicale
stem cells and in vivo directly to oligodendrocytes; INSERM U561 Service Pdiatrie C
g) to evaluate the ability of autologous mesenchymal stem cells as a Hopital Saint Vincent de Paul
potential treatment for presymptomatic and adult X-ALD patients; Paris, France
h) to identify drugs that can stimulate the expression of the ALD-related Dr Pujol,Aurora
gene. Institut de Recerca Oncologica (IRO)
Centre de Genetica Medica i Molecular (CGMM)
Hospitalet de Llobregat
Potential applications Llobregat, Spain
and expected results Prof. Nave, Klaus-Armin
Prediction of the phenotype will allow the establishment of a preventive Max Planck-Gesellschaft zur Frderung der Wissenschaft e.V.
and phenotype-adapted treatment for all X-ALD patients identified at Department of Neurogenetics
birth by systematic screening. X-ALD patients already have increased Max Plank Institute for Experimental Medicine
VLCFA levels at birth, which would enable neonatal screening. Gttingen, Germany
Furthermore, clarification of the pathogenesis of X-ALD and the Prof.Wanders, Ron J A
development of new models of X-ALD will allow new therapeutic
Academic Medical Center
strategies to be developed and the efficacy of the current envisaged
University Hospital Amsterdam
therapeutic approaches to be tested. Preliminary results obtained with
ALD gene transfer in X-ALD CD34+ cells and with the pharmacological Department of Pediatrics
up-regulation of the Aldr gene in Ald-deficient mice suggest that these Laboratory for Genetic Metabolic Diseases,
studies will lead to phase I/II clinical trials in X-ALD patients. Amsterdam,The Netherlands
Dr. Geigle, Peter
CELLMED AG
Alzenau, Germany
Acronym: X-ALD
Duration: 36 months

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BRAIN, NEUROLOGICAL PainGenes

AND PSYCHIATRIC
DISEASES
Heritability of chronic neuropathic pain

Summary state or degree of tissue injury. That is, we will investigate pain
susceptibility genes rather than disease susceptibility genes. Such
Chronic pain undermines the health and welfare of millions of EU genes, and the neural processes with which they are associated, are
citizens and carries enormous financial costs. Individual variability in expected to affect pain intensity irrespective of the proximate cause
the burden of pain has traditionally been attributed to psychosocial of the neural damage: trauma, surgery, neoplasm, infection or disease.
factors. However, new data indicate that there is an important
Results will provide essential background for the development of novel
heritable predisposition to pain, particularly to the development of
prognostic,diagnostic and treatment options for chronic pain sufferers,
chronic pain after neural injury (neuropathic pain). Pain susceptibility
with major benefits also for their families, employers and European
genes are intrinsically hard to detect in human lineages and
economies.
populations.This STREP adopts the alternative approach of exploiting
new rodent models of neuropathy to uncover pain susceptibility loci
and associated neurobiological processes, using
inbred mouse strains that show high versus low pain
phenotypes.
Linkage analysis and positional cloning, together

with expression arrays and a variety of electro-
physiological and neurochemical methods applied to
primary sensory neurons, will be used to identify
the biological causes of contrasting pain phenotype.
The strategy is to identify genetic and cellular
variables that co-vary with pain phenotypes across
strains. With mouse candidate genes in hand,
identification of the human orthologs is feasible.We
stress that our project does not aim to find genes
that affect susceptibility to specific disease entities
that may be painful. Rather, we focus on genes and
processes that determine the amount of pain felt
by an individual in the presence of a specific disease
Different strains of inbred mice show dramatic, heritable, differences in pain sensitivity.
A? Response of 11 mouse trains tested in the neuroma pain model. B.The same strains
tested for neuropathic tactile hypersensitivity on the hindpaw. Analysis of across strain
correlations and differences can illuminate pain genetics.

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Coordinator Fried, Kaj

Devor, Marshall
Center for Oral Biology, Novum
Hebrew University of Jerusalem
Karolinska Institutet,
Department of Cell and Animal Biology
Huddinge, Sweden
Institute of Life Sciences, Reeh, Peter
Jerusalem 91904, Israel University of Erlangen-Nuremberg
E-mail: marshlu@vms.huji.ac.il Institute of Physiology and Experimental Pathophysiology
Key words: chronic pain, gene, microarray, nociception, Erlangen, Germany
neuropathic pain, neuropathy, pain, pain sus- Peth, Gabor
ceptibility University of Pecs
Department of Pharmacology and Pharmacotherapy
Partners Faculty of Medicine,
JDarvasi, Ariel Pecs, Hungary
Hebrew University of Jerusalem Michaelis, Martin
Department of Ecology, Systematics and Evolution (ESE) Aventis Pharma Deutschland GmbH
Institute of Life Sciences Frankfurt/Main, Germany
Jerusalem, Israel
Yakir, Benjamin
Acronym: PainGenes
Hebrew University of Jerusalem Project number: LSHM-CT-2004-502800
Department of Statistics EC contribution: 1 600 000
Jerusalem, Israel Duration: 36 months
Tal, Michael
Hebrew University-Hadassah Jerusalem Israel
Department of Anatomy and Cell Biology
Schools of Medicine and Dentistry
Ein Kerem, Jerusalem
Wiesenfeld-Hallin, Zsuzsanna
Department of Laboratory Medicine
Division of Clinical Neurophysiology
Huddinge University Hospital
Stockholm, Sweden

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BRAIN, NEUROLOGICAL GRIPANNT

AND PSYCHIATRIC
DISEASES
Glutamate receptor interacting proteins as novel

neuroprotective targets
Summary Project main goals

Excitotoxicity contributes significantly to neuronal cell death in a Excitotoxicity contributes significantly to neuronal cell death in a number
of neurological conditions including stroke, head trauma, and
number of neurological conditions including stroke, head trauma, and Huntingtons disease.The recent discovery of proteins that anchor and
Huntingtons disease.The recent discovery of the proteins that anchor interact with glutamate receptors opens a new strategic approach to
and interact with glutamate receptors opens a new strategical cytoprotective therapy. The present project aims at exploiting this
conceptual advance to provide a platform for cytoprotective therapies
approach to cytoprotective therapy. The present project aims at
that do not interfere unduly with synaptic transmission.
exploiting this conceptual advance to provide a platform for
cytoprotective therapies that do not interfere unduly with synaptic
Key issues
transmission.
The main objective of the present project is to exploit the recent
Glutamate receptor interacting proteins (interactors) serve dual advances in this field to provide a platform for cytoprotective therapies
purposes. They determine the level and site of glutamate receptor that do not interfere unduly with synaptic transmission.
expression within the cells and connect the receptors to specific Measurable objectives (detailed below) include:
intracellular signalling pathways. Both roles are interesting from a identification of at least five new proteins that interact with glutamate
therapeutical perspective.Thus, excitotoxicity might be alleviated by receptors;
modulation of the surface expression of glutamate receptors, as well unravelling the precise mechanisms for at least five protein-protein
as by interfering with their downstream signalling. interactions in supramolecular glutamate complexes;
identification and characterisation of five different tools for
The first part of the project aims at providing a more complete picture interfering with protein-protein interactions;
of the functional roles of interactors (WP1-3). It is envisaged that we
identification of at least ten putative pro-survival genes;
will be able to identify novel interactors and that we will be in a
evaluating the cytoprotective potential of the above tools and targets
position to understand, at a molecular level, how the different
in in vitro models;
interactors connect with glutamate receptors and with each other.
test tools and targets with cytoprotective potential in whole animal
This part of the project will also elucidate the principles that govern ischemia models, ending up with at least three novel strategies with
the turnover and surface expression of glutamate receptors and the obvious clinical potential.
mechanisms that couple the individual receptors to specific The novel strategies thus identified will be of obvious commercial
downstream effectors of excitotoxicity. potential.The further development and clinical assessment of these
is outside the scope of the present project.
The second part (WP4 and 5) aims at exploiting the increased insight
It is envisaged that the project as a whole will considerably increase our
obtained through the first part of the project to design ways to understanding of the molecular and cellular mechanisms and pathways
alleviate excitotoxicity in different model systems. In designing these in excitatory amino acid induced cell death and neuronal survival.
experiments the complex of glutamate receptor interacting proteins This project is divided in two parts.The objective of the first part is
will be viewed as a nodal point in orchestrating the surface expression to obtain a more complete picture of the functional roles of
interactors.The objective of the second part is to exploit the increased
of receptors and in activating appropriate and inappropriate
insight obtained through the first part of the project to design ways
(excitotoxic) signalling pathways. to alleviate excitotoxicity in different model systems.In designing these
experiments the complex of glutamate receptor interacting proteins
The present project will be based on a unique combination of methods
will be viewed as a nodal point in orchestrating the surface expression
that draws full advantage of the technological advances made over of receptors and in activating appropriate and inappropriate
the last few years. (excitotoxic) signalling pathways.

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Technical approach
The project also has several objectives in relation to technology
Partners
development. Henley, Jeremy
Thus we will: Bristol University
design and use blocking peptides to disrupt specific protein:protein Senate House
binding events involving defined glutamate receptor subunits and, if
Bristol, United Kingdom
appropriate, down-stream protein interactions;
Rnn, Lars Christian
use and further develop fluorophore technology such as spectral
variants of GFP, pH-sensitive GFP (pHluorin) and photoactivatable NeuroSearch A/S
GFP (PA-GFP) to monitor protein movement in neurons;
Ballerup, Denmark
design and optimise siRNAs and hairpins for the targeted knock-
Kaczmarek, Leszek
down of specific proteins;
Instytut Biologii Doswiadczalnej im. M. Nenckiego PAN
exploit viral delivery systems for highly efficient expression of
peptides, modified proteins or siRNAs in neurons in culture and in Warsaw, Poland
vivo;
Bading, Hilmar
make use of existing and newly developed transgenic mice that either
Heidelberg University
lack specific protein(s) or express modified versions of proteins of
interest (e.g. epitope-tagged GluRs). Heidelberg, Germany
Pin, Jean Baptiste
Expected achievements/impact Fluofarma SA
The potential impact of identifying novel strategies for cytoprotective Pessac, France
therapy is enormous.
Roepstorff, Peter
After more than two decades of intensive research we are still left
without a single cytoprotective drug for clinical use. Should we University of Southern Denmark
succeed in identifying novel approaches to curb excitotoxicity, and Odense M, Denmark
should these strategies eventually prove useful in a clinical setting, the
impact would be on a par with the discovery of the first Choquet, Daniel and Mulle, Christophe
antihypertensive drugs. CNRS
Paris, France
Bordeaux, France
Coordinator Davanger, Svend
Petter Ottersen, Ole
Universitetet i Oslo
University of Oslo
CMBN
CMBN
Blindern, Norway
Postboks 1105 Blindern
0317, Norway
Phone: +47 22851299 Acronym: GRIPANNT
Fax.+47 22851488 EC contribution: 1 785 000
E-mail: o.p.ottersen@medisin.uio.no Duration: 36 months

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BRAIN, NEUROLOGICAL STRESSPROTECT

AND PSYCHIATRIC
DISEASES
Inhibition of stress activated protein kinase signalling as

a therapeutic strategy against exitotoxicity
Summary Background
Excitotoxicity (EXC), neuronal death from excessive stimulation, To achieve clinically useful neuroprotection against excitotoxicity
(EXC) is currently one of the major challenges to medical research.
contributes to a plethora of neurodegenerative conditions including It is the main mechanism underlying neuronal death in all
cerebral ischemia and seizure-induced death. Stress-activated hypoxic/ischemic and traumatic brain damage and in epilepsy, and
protein kinases (SAPKs) of the JNK and p38 families have been contributes also to most neurodegenerative diseases.EXC is triggered
by the excessive activation of ionotropic glutamate-receptors,
identified as novel mediators of EXC death which is mainly executed
particularly the NMDA (N-methyl-D-aspartate) subtype, but the
by existing proteins demanding post-translational modifications. propagation of intraneuronal signalling to degenerative execution
STRESSPROTECT members have (a) demonstrated that specific remains obscure.
TAT-fused peptide inhibitors of the JNK pathway confer lasting Despite intensive study of the mechanisms of EXC and considerable
neuroprotection against seizure-induced and ischemic cell death success at neuroprotection in animal models, there are no approved
current treatments against EXC in humans,and neuropharmacological
with an extended therapeutic window, (b) analysed the individual
treatments of epilepic disorders do not confer anti-excitotoxicity.The
apoptotic actions of SAPK isoforms, and (c) provided important reasons for these failures are multiple, but we would mention two of
insights into signalling from glutamate-receptors. STRESSPROTECT the main problems.
gathers the European elite for SAPK signalling in the brain and for Unwanted side effects of the neuroprotection: drugs that inhibit
neuroprotection against EXC by pharmacological intervention in the NMDA receptor itself cause psychotic-like reactions and
memory loss in humans; and in animal models, while these drugs
these pathways, and proposes a novel therapeutic concept against
do rescue some neurons, they also cause the vacuolation and even
EXC. STRESSPROTECT provides synergistic research activities the death of others.
addressing the organisation and function of SAPKs signalling with
Shortness of the therapeutic time-window: these NMDA antagonists
molecular genetics, proteomics, signalosome-analysis, and molecular are generally found to be ineffective if given more than 2-3 hours after
pharmacology including pharmacokinetics. At the end the onset of the ischemic event, which is too short for most practical
STRESSPROTECT has identified EXC-related SAPK signalosomes purposes. Most of the neuronal death occurs much later than this 2-
3 our limit, reflecting complex pathways between the initial calcium
and delivered novel inhibitor peptides against SAPK signalling entry and the ultimate death effectors, and it seems plausible that a
underlying EXC-mediated degeneration. STRESSPROTECT will longer time window and a reduction in side-effects might be achieved
identify (a) proteins in upstream regulatory complexes induced by by targeting specific stress-activated pathways well downstream of the
initial calcium-activated events.
EXC, (b) the downstream targets mediating EXC, (c) specific
protein-protein interaction sequences as targets for functional Recently, this strategy has been adopted by members of this
consortium, focusing on the c-Jun N-terminal kinase (JNK) pathway.
inhibition of SAPK signalling, (d) extend the neuroprotective value
This led to the demonstration that peptide inhibitors of the pathway
of existing inhibitory peptides, (e) develop novel TAT-fused peptides protect against several forms of EXC, and in particular confer strong
inhibiting particular loci in the stress kinase pathways, (f) devise ways protection against ischemic cell death even when administered 6-12
of targeting peptides specifically into EXC-affected cells and (g) hours after the insult. Despite the promise of this neuroprotective
therapy, which could in principle already be extended to clinical trials,
carefully defines the risk-benefit ratio prospective to it has to be admitted that the underlying cell biology is still largely
implementation in clinical trials. unknown and it is unclear whether it can be extended to other EXC-

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DISEASES
related conditions.Furthermore,there is evidence that a second MAP is very high, not only due to the high incidence of the disorder, but
kinase pathway, p38, is also involved in cerebral ischemia and other also due to its long-term detrimental consequences. In the United
excitotoxic conditions. And while no negative side-effects of the Kingdom,it has been calculated that the care for every patient affected
peptide inhibitors have so far been discovered, they cannot be by stroke costs more than 15 000 pounds over five years, informal
discounted. Hence, more research is needed to clarify the signalling care costs excluded. In Sweden and in the Netherlands, special
pathways involved in a variety of cell biological and clinically relevant computer or statistical models have been implemented in order to
excitotoxicity models,and techniques need to be developed to target tackle the difficulties related to cost-evaluation of stroke at the national
specifically the cells and pathways responsible for excitotoxicity- level. In the United States, is has been evaluated that the cost of stroke
related degeneration while sparing healthy cells and pathways without during 2003 will be $51 billion with more than $6 billion for informal
deleterious action. care-giving. In Taiwan, it has been calculated that the median cost per
patient can be multiplied by a factor of approximately 15 depending
The project will bring together cell and molecular biologists,cell death
on stroke severity as assessed by the initial neurological score.
experts, neuropharmacologists and neurobiologists with expertise in
cerebral ischemia and seizures and in behavioural analysis, to analyse As already discussed, current therapeutic strategies are hardly
the two main stress kinase pathways (JNK and p38) at molecular, effective, difficult to use (mainly due to a short therapeutic window
cellular and system levels. The ultimate aim will be to develop following stroke), and may have serious side-effects, including
neuroprotective peptide drugs and effective protocols to be evaluated potentially lethal consequences.The advent of new therapies based
in rodent models of focal cerebral ischemia and kainate-induced on JNK inhibitors with negligible side-effects and extended therapeutic
epilepsy.The projects goals addresses all the objectives. It proposes window may drastically influence both stroke consequences and
a novel therapeutic concept against excitotoxicity (EXC) in particular societal cost.As already discussed, cell-penetrating inhibitors of JNKs
following ischemia and seizure. STRESSPROTECT will develop novel proved to be protective when administered 6 to 12 hours after
pharmacological inhibitors against stress kinases (p38 and JNK). cerebral ischemia in neonatal and adult rodents. If confirmed in
STRESSPROTECT provides synergistic research activities addressing humans, such an extended therapeutic window would profoundly
the organisation and function of SAPKs signalling with molecular modify the treatment opportunities against stroke. Today, a limit of
genetics, proteomics, signalosome-analysis and molecular three hours after thrombolytic treatment strongly reduces the
pharmacology including pharmacokinetics. number of patients susceptible to benefit from the intervention.The
extended neuroprotective effects of treatment using JNK inhibitors
would dramatically increase the number of patients which could be
Expected results treated before the end of the therapeutic window.As a consequence,
JNK inhibitors do not simply represent a new treatment strategy with
EXC is involved in almost all neurodegenerative diseases and
increased potency as compared with current therapies, but may
processes. Nevertheless, our proposal focuses on ischemia and
increase the population of patients that may be treated. Finally, the
kainate-induced seizures as classical models of EXC. In consequence,
identification of peptide sequences for inhibition of specific kinases
STRESSPROTECT exemplifies the potential impact of basic research
signalling will open a novel field of pharmacological approaches and
on clinically relevant diseases. biological activities.
Cerebrovascular disorders constitute a worldwide health problem.
According to the French College of Neurological Teachers, stroke
constitutes the third largest cause of mortality, with about 150 000
new cases every year in France. In Belgium, the annual incidence of The development of domain-specific peptide inhibitors will selectively
stroke falls between 200-230 per 100 000 inhabitants,with a mortality target pathological signalosoms with a limited risk for side effects.Such
rate of 21% and 30% of affected patients becoming dependent on inhibitors might be useful for neurological and non-neurological
others. In Italy, the incidence of stroke is about 10 in 100 000, with less diseases.
than 5% of strokes occuring in subjects younger than 45 years. In
Switzerland, more than 12 000 new cases occur per year (AZPD
Astrazeneca). In the United States, stroke ranks also in third position
as a cause of death and more than 600 000 cases were recorded during
1997 (National Center for Health Statistics).It has been calculated that
a stroke occurs every 53 seconds in North America.The cost of stroke

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Coordinator Dr Coffey, Eleanor

Prof. Herdegen,Thomas Turku Centre for Biotechnology
Department of Pharmacology Turku, Finland
University of Kiel Dr Courtney, Michael
Hospitalstrasse 4 Department of Neurobiology
24105 Kiel, Germany A.I.Virtanen Institute
Phone: + 49 431 597 3502 Kuopio, Finland
Fax: + 49 431 597 3522 Dr Hardingham, Giles Edward
E-mail:t.herdegen@pharmakologie.uni-kiel.de Department of Preclinical Veterinary Sciences
Key words: excitotoxicity, genomics, neurodegeneration, University of Edinburgh
proteomics, stroke, stress kinases Edinburgh, United Kingdom
Prof.Vercelli,Alessandro
Partners
Department of Anatomy
JDr Bonny, Christophe
University of Turin
Unit of Molecular Genetics
Turin, Italy
University of Lausanne
Lausanne, Switzerland
Dr Castagn,Vincent Acronym: STRESSPROTECT
Porsolt SAS EC contribution: 1 499 560
Le Genest-Saint-Isle, France Duration: 36 months
Prof. Clarke, Peter Geoffrey
Department of Cell Biology

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INTERDEVO BRAIN, NEUROLOGICAL

AND PSYCHIATRIC
DISEASES
Gene networks in cortical interneuron development:

modeling interneuron function in health and disease
Summary Thus, the study of cortical development is important, not only to

further our understanding of this complex phenomenon, but because
The neural assembly underlying the formation of functional networks cortical malformations are now recognised as causing significant
proportions of cognitive and neurological disorders.
in the cerebral cortex constitutes one of the most complex neuronal
systems in the brain.Much of this complexity arises during development Until the discovery that projection neurons and interneurons of the
cerebral cortex follow different developmental programmes
through the interaction of two distinct neuronal types,the glutamatergic (reviewed in Marn & Rubenstein Nat Rev Neurosci 2: 780-90, 2001),
projection neurons and aminobutyric containing (GABAergic) the analysis of cortical malformations was observed from a unitary
interneurons. Recently interneuron dysfunction has been associated perspective, i.e. gene mutations would affect equally the development
of both projection neurons and interneurons, producing cortical
with severe neurological and psychiatric disorders (e.g. epilepsy,
dysfunction.The recent findings on the subcortical origin of cortical
schizophrenia and bipolar disorder). In order to achieve true progress interneurons, however, have provided with a new standpoint to
in the understanding of cortical development and of neurological understand cortical disorders. In this new context, gene mutations
affecting cortical projection neurons would not necessarily perturb
diseases associated with cortical interneuron dysfunction, a complete
the development of cortical interneurons, and vice versa. This later
account of the development of its neuronal constituents is essential. In observation is extremely important for the understanding of complex
that sense, despite the detailed picture that is emerging about the cortical disorders, since it is becoming evident that gene mutations
development of cortical projection neurons, the mechanisms exclusively affecting the development of a given subtype of cortical
interneurons would not cause macroscopic malformations in the
underlying the development of interneurons in the cerebral cortex have cerebral cortex, and therefore would be impossible to detect with
remained poorly defined.The overall goal of our project is to obtain a standard imaging techniques (e.g. fMRI). Obviously, the fact that the
comprehensive definition of the cellular and molecular mechanisms cerebral cortex looks grossly normal does not mean that its function
is also normal. Indeed, dysfunction of cortical interneurons has been
controlling the development of cortical interneurons. With the recently associated with severe neurological conditions (e.g.epilepsy),
information obtained from the analysis of the normal development of and important psychiatric disorders, such as schizophrenia or bipolar
cortical interneurons,we also plan to generate mouse models to study disorder (Benes & Berretta Neuropsychopharmacology 25:1-27,2001.).
In schizophrenia, for example, morphological abnormalities are
the consequences of cortical interneuron deficiency.
relatively subtle.Nevertheless,there is increasing evidence suggesting
that GABAergic neurotransmission is altered in the prefrontal cortex
of schizophrenic patients. Specifically, a number of post-mortem
Migrating cortical studies suggest that the number, distribution, neurochemistry or
GABAergic interneurons in synaptogenesis of cortical GABAergic interneurons could be altered
culture.The image shows in schizophrenia (Lewis & Lieberman, Neuron 28: 325-34, 2000).Thus,
the typical morphology of elucidating the mechanisms that regulate development of cortical
migrating cells, with a long interneurons is likely to be essential for understanding and, eventually
leading process and a treating, major psychiatric disorders.
short trailing process.
Cortical interneurons have Aim
always the same morphol-
ogy when migrating. The general goal of the project is to obtain a comprehensive definition
of the cellular and molecular mechanisms controlling the
development of cortical interneurons.To reach this aim, we will take
a multidisciplinary approach by combining novel bioinformatic and
Background genomics applications, cutting-edge imaging techniques, and
conventional cellular, molecular and electrophysiological
Defects in cortical neural circuitry are most likely to underlie
methodologies. In addition, we will develop new genetic tools to
important neurological and psychiatric illnesses, such as epilepsy,
engineer developmental models of cortical disorders involving
schizophrenia and major affective disorders. Remarkably, a rapidly
interneuron deficiency.
growing body of data suggests that some of these defects may arise
as a consequence of abnormal development of the cerebral cortex.

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DISEASES
Expected results
Successful execution of the project will result in: i) new knowledge
Coordinator
of the mechanisms underlying the specification,migration and terminal Dr Marn, Oscar
differentiation of cortical interneurons, and ii) generation of new
developmental models of cortical disorders resulting from Consejo Superior de Investigaciones Cientficas and
interneuron deficiency. Universidad Miguel Hernndez
Instituto de Neurociencias de Alicante
Potential applications Universidad Miguel Hernndez, Campus de San Juan
There is increasing evidence suggesting that research on the development 03550 San Juan de Alicante, Spain
of cortical interneurons is fundamental for understanding the etiology Phone: + 34 96 591 9384
of a number of important human disorders, ranging from epilepsy or
learning disabilities to major psychiatric illnesses such as schizophrenia, Fax: + 34 96 591 9561
bipolar disorder or autism. In addition to increasing knowledge on the E-mail: o.marin@umh.es
basic mechanisms controlling the development of cortical interneurons,
our research programme goes one step further in trying to exploit the Key words: brain development, cerebral cortex,
full potential of genome information to underpin applications to human GABAergic interneuron, neurological disor-
health.Thus, the production of mouse models of cortical interneuron ders, epilepsy, schizophrenia, patterning,
deficiency will have a clear impact on improving the diagnosis and migration, synaptogenesis, neurophysiology
understanding of human cortical developmental disorders.
Partners
Foundation for Research and Technology Hellas,
University of Crete Medical School and Institute of
Molecular Biology and Biotechnology, Heraklion, Greece
Medical Research Council, London, United Kingdom
MRC Anatomical Neuropharmacology Unit, Oxford,
United Kingdom
Ecole Normale Superieure and Centre National de la
Recherche Scientifique, UMR 8542, Rgionalisation
Nerveuse, Paris, France
Oryzon Genomics, Barcelona, Spain
Differentiated cortical neurons in culture.The image shows an example
Fundacin para la Investigacin Biomdica del Hospital
of one of the possible morphological phenotypes observed in differenti- Universitario Ramn y Cajal, Madrid, Spain
ated cortical neurons. Multiple genes control the fate of distinct cortical
interneurons, determining their morphology, location and connections. Telethon Institute of Genetics and Medicine, Naples, Italy
Acronym: INTERDEVO
Duration: 36 months

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NeuroDisseminator BRAIN, NEUROLOGICAL

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DISEASES
Neuroimaging laboratories sharing data

through a database
With metaresearch across studies, one may gain new knowledge about
Sagittal view of the cerebral cortex and its functions.New hypotheses can thus be made
somatosensory by combining the results from different functional experiments.This is
activations only possible with the proper tools, such as the NeuroDisseminator
from the visualiser and query tool.A possible application is to use the database
Neuro- to find new hypotheses about the cerebral cortex.
Generator
database
3D view of somatosensory
activations from the
Summary NeuroGenerator database
The NeuroDisseminator project aims at creating functional maps of

the human cerebral cortex by analysing PET and fMRI studies in a
homogenous way. The studies are submitted from collaborating
laboratories in Europe, and the statistical results are stored on a
database distributed on DVD to all contributors.
Coordinator
Prof. Roland, Per
Background Karolinska Institutet
The main objective in functional neuroimaging is to map the location of Division of Brain Research
cerebral functions. However, a single study only reveals just a few Department of Neuroscience
functions for some regions while these regions are probably contributing Retzius vg 8, SE
to many more functions,together with other regions in a larger network. 171 77 Stockholm, Sweden
NeuroDisseminator solves this issue by collecting many functional PET Phone: + 46 8 5248 7785
and fMRI studies from a number of laboratories in Europe and analyses Fax: + 46 30 90 45
them in a homogenous way.The statistical results are stored in a database
E-mail: per.roland@neuro.ki.se
called NeuroGenerator, which can be accessed with a visualisation and
query tool.It is possible for the submitters to access the database through Project web-site: www.neurogenerator.org
the Internet and it is also distributed on DVD to all the contributors. Key words: PET, fMRI, database, cerebral cortex,
functional neuroimaging
Aim
Partners
The overall aim of the NeuroDisseminator project is to create a Svensson
functional map of the cerebral cortex.This is only possible by collecting
Center for Parallel Computers
many PET and fMRI studies.Thus,the NeuroDisseminator project now
aims at increasing the number of studies in the NeuroGenerator Royal Institute of Technology
database and distributing the database to the collaborators. Another Stockholm, Sweden
goal is to perform research and develop ideas regarding meta-analysis
of these studies.
Expected results Acronym: NeuroDisseminator

The first version of the database has already been distributed,containing EC contribution: 400 000
a fraction of the experiments collected so far.We expect to release a Instrument: Specific Support Action
Duration: 36 months
second version soon.Within the NeuroDisseminator project, we also Starting date: 01/01/2004
expect to publish some meta-analysis studies

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First European meeting on molecular

and cellular cognition
Summary mance and/or low IQ scores. Finally, drug addiction and alcohol abuse
are believed to have a strong cognitive component, significantly
Molecular and cellular cognition is a rapidly moving research area which affecting relapse and mental dependence.The convergence between
brain pathology and cognitive dysfunction is possibly even more
is at a crossroads between basic neurobiology and clinical
evident at cellular and molecular level. It is widely believed that the
neuroscience. At the end of 2002 a new scientific organisation, the large majority of mental disorders are complex and often chronic
Molecular and Cellular Cognition Society (MCCS,www.molcellcog.org), diseases, caused by maladaptive changes in information processing,
which result in functional and often anatomical alterations at the level
was established with the aim of facilitating exchanges between
of neural circuitry and neuronal signalling.The field of molecular and
laboratories in this research field and to promote neuroscience at the cellular cognition has been one of the first contemporary
general public level.This document deals with the organisation of the neuroscience branches to combine molecular and behavioural
first European Meeting, as a satellite of the Federation of European approaches to study inter- and intracellular communication and to
have significantly contributed to clarify long-term mechanisms of
Neuroscience Societies (FENS) meeting, effectively held in Lisbon on synaptic adaptation. Quantitative analyses of behavioural parameters
8-9 July 2004.On day 1,the first oral presentation session was followed by means of pharmacological and electrophysiological tools have been
in the afternoon by a single poster session. On day 2, two oral enhanced, starting from the early 1990s, by new powerful genetic
techniques such as gene targeting and transgenesis in the mouse.These
presentation sessions were scheduled, for a total of 21 speakers, 100 technologies have been introduced with enormous success and
posters and 300 participants.In addition to invited speakers coming from provided important experimental evidence that molecular changes in
Europe, Japan and USA, one third of the oral presentation had been specific brain areas underlay changes in synaptic plasticity, cognition
and behavioural responses. For instance, mouse mutants for the
selected from posters. Eight fellowships were awarded to junior
transcription factor CREB have been useful not only in determining
scientists allowing them to participate in the meeting. the role of gene expression in memory formation and consolidation
but also to study its role in brain diseases such drug addiction and
mood disorders. Moreover, the technologies of conditional and
Background reversible mutagenesis in vivo that have been especially developed in
A major emphasis of the LifeSciHealth Priority area studying the brain memory research to circumvent developmental side-effects of the
and combating diseases of the nervous system, which must be mutations studied are now available to study long-term neural changes
implemented within the 6th Framework Programme, is fully justified associated with neuropsychiatric disorders. Conversely, genetically
by the increased prevalence of neuropsychiatric diseases in highly modified mouse strains,such as knock-out for monoamine receptors,
developed countries. Recent statistics considering disability rather that were originally generated to study psychiatric disorders such as
than mortality in our society place eight brain disorders amongst the addiction and anxiety,may be also useful to dissect cognitive processes.
first ten most relevant diseases, including major depression,
The advent of post-genomic and proteomic analyses hold
neurodegeneration (mainly Alzheimers and Parkinsons), alcohol and
considerable promise for the study of the cellular and molecular
drug abuse.
events that regulate synaptic activity and behaviour. Identification of
Despite the apparent heterogeneity at the clinical
level, research in neuroscience of the last decade
has clearly demonstrated that most of these brain
disorders share some common symptoms at the
level of cognition, which in a broad sense includes
both explicit and implicit forms of learning and
memory.Indeed,clinical assessment for depression
and Alzheimers disease often consider loss of
memory and emotional disturbances as important
early pathological evidence while patients affected
by other diseases such as Parkinsons and
Huntingtons always manifest cognitive symptoms
at end stages.Moreover,early onset disorders such
as attention deficit hyperactivity disorder (ADHD),
mental retardation and epilepsy invariably correlate
in their severe forms with poor school perfor-

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i) Fostering European research

in the field of molecular and
cellular cognition
The birth of the field of molecular
cognition was in 1992 with the
seminal papers of Alcino Silva
(Susumu Tonegawas laboratory,
Nobel laureate) and Seth Grant
(Eric Kandels laboratory, Nobel
laureate) on the CaMKII and Fyn
protein kinases knockout mice,
respectively. Although previous
research by means of pharma-
cological inhibitors started to
investigate the behavioural cor-
relates of drug action, Silva and
Grant for the first time
demonstrated that the loss of
intracellular signalling molecules
may produce deficits in long-term
plasticity and long-term memory.
Despite the meteoric development
over the last decade of this field in
the USA, a significant lag exists in
specific gene products in subsets of neurons that may be activated Europe, where only few laboratories have used molecular and genetic
upon learning is a major technological and economical challenge which approaches to dissect cognitive processes in experimental animal
needs to be developed in collaboration with pharmaceutical models.This is particularly disappointing since European research has
companies. In this respect, one of the proponents of the present always been a leading force in neuropsychopharmacology, both in
application has pioneered this approach. Our precise understanding academia (e.g. Daniel Bovet, Nobel Laureate) and in pharmaceutical
at the cellular level of the molecular mechanisms underlying normal industries.The organisation of the first European meeting in Molecular
and pathological synaptic plasticity in discrete brain areas is readily and Cellular Cognition has therefore the crucial goal of helping to fill
becoming an essential goal for identifying new, more specific drug the gap between US and European research in this new field.Additionally,
targets for innovative treatments.However,validation of new potential this important meeting will also promote interchanges among American
targets as well as the development of new drugs will necessarily and European laboratories.
require appropriate animal models, in which the relevant molecules
have been either deleted from the brain or modified in their ii) Developing interactions between pharmaceutical industry
expression level, activity, or structure. Finally, to process all this and basic research
information and integrate it in a coherent picture of the cognitive Although it is always difficult for individual researchers to establish
processes that range from molecules to mind, it will be necessary to fruitful industrial connections as mentioned above, this is perhaps
exploit innovative neuroinformatic and statistical tools. more so in the rapidly evolving field of molecular cognition, where
For all these reasons we believe that the first European Meeting on there is great opportunity for translational research. It is obvious that
Molecular and Cellular Cognition is an excellent opportunity for the scientific platform we are proposing may provide the ideal setting
developing this research field in our continent and it will provide an for a closer interaction between the academic world and the European
opportunity for the clinical and pharmaceutical world, as well as for industries interested in neuroscience.
junior researchers,to interact with top scientists coming from Europe, iii) Interacting with psychiatrists, neurologists and
North America and Japan. neuropsychologists
One of the main goals of our meeting is to create an interface between
Aim basic scientists and clinicians. Just as an example, the recent
experimental evidence provided by Nader, Ledoux and Alberini that
Our aim is to provide a European forum for the development of consolidated memories can be weakened by pharmacological
molecular and cellular approaches to study cognition, emotion and treatment during subsequent recall have considerable clinical
behaviour.Furthermore,we believe that a significant integration at this potential. However, rigorous clinical research is needed before these
level between basic science, pharmaceutical research and clinical findings can be shown to be clinically relevant.Stimulating interactions
science will provide theoretical and practical foundations for future with clinicians is therefore a priority of our proposal and their
treatments of neurological and psychiatric disorders. participation in the meeting is highly encouraged.

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iv) Providing additional opportunities for women and eastern In addition to this meeting,the Molecular and Cellular Cognition Society
European scientists would like to continue to foster the field in Europe through future
initiatives and meetings, as well as having a role in the education of the
Women scientists are underrepresented, especially at the principal
general public on key findings in the field, including their limitations and
investigator and/or professorial level in most areas of science. Indeed,
implications for health and society.We strongly believe that good science
this is true in the field of cellular molecular cognition and we are
cannot be self-sustaining.On the contrary,the best of research can only
working toward reverting this trend. For example, of the seven
be achieved by frank and open interactions between scientists and the
scientists involved in the organisation of the meeting, only two are
general public.This is particularly true for issues concerning cognitive
women. In addition, with the future enlargement of the European
neuroscience, a natural focal point for discussion and debate for the
Union to eastern European countries it is also a high priority for us
humanities and the natural sciences. For example, philosophical and
to involve researchers from those nations.Therefore, we plan to act
health-related questions, such as the mind-body problem, the role of
in two ways. First, we will provide fellowships to encourage female
psychoactive drugs in medicine and recreation, the impact of
scientists and eastern Europeans workers to come to this meeting.
neuropsychiatric diseases and their medication,have a far-reaching impact
Second, we will select their most interesting posters for oral
on health, ethics, legislation and on society in general.
presentations. Due to the often prohibitive costs of attending North
American meetings, this may be the only chance for many potentially
outstanding investigators from these groups to meet leading scientists
in the field in such a context. This meeting will also be useful for
establishing personal contacts as a prerequisite for future job
Coordinator
opportunities (e.g. postdoctoral training) and collaborations. Brambilla, Riccardo
Centro San Raffaele del Monte Tabor
Expected results and potential San Raffaele Research Institute
applications Va Olgettina 58
The impact of brain disorders on cognition, emotion, behaviour and
20132 Milano, Italy
public health is enormous.Changing demographics in European countries
makes it imperative to decrease the morbidity of the aged population. Phone: + 39 0226 434 876
As the proportion of people over retirement age increases, so will the
Fax: + 39 0226 434 767
burden of supporting them, borne largely by those in the workforce.
Reducing the morbidity of neurodegenerative diseases is clearly a critical E-mail: r.brambilla@hsr.it
public health issue in developed countries.Cognitive decline in the elderly
is one of the most immediate and destructive symptoms, often being a
prelude to dementia and loss of independence, putting a major burden Project web-site: www.molcellcog.org
on families and on the healthcare system. Similarly, the ability of people
Key words: molecular and cellular cognition, learning
of working age and younger to contribute to society must be sustained.
and memory, neuronal plasticity, psychiatric
Psychiatric disturbances such as mood disorders and addiction to drugs
diseases
and alcohol are a major impediment to this contribution,and one of the
most destructive influences in society.This fundamental knowledge is a
sine qua non,in the immensely complex field of psycho-therapeutics,for
the creation of strategies which might decrease,if not eliminate problems
Acronym: EUROMEMO
arising from these disorders, that affect so devastatingly both the
individual and society. Understanding the basic molecular and cellular EC contribution: 19 650
mechanisms of normal and pathological brain function is now a key goal Instrument: Specific Support Action
of animal model studies.Most currently available technologies have been Duration: 18 months
applied in the field of learning and memory, in which quantitative and
reproducible tests are available to measure objective behavioural
outputs.While it is not predictable at present as to what extent which
of these studies may lead to the discovery of new treatments for
disorders of the nervous system, it is nevertheless very important that
Europe foments the interaction between basic research,clinical research
and the industrial world. Such interactions will provide the basis for
effective translational research in the field of memory and cognition and
at the same time will create new opportunities for developing small- to
medium-size biotechnology companies devoted to specific tasks, such
identification of early diagnosis tools for neurodegenerative diseases or
discovery of drugs improving memory, mood or attention.

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ESNI course 2003 BRAIN, NEUROLOGICAL

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DISEASES
European School of Neuroimmunology (ESNI);

4th Teaching Course Barcelona
Neuroimmunology aims to define the mechanisms underlying the The 4th ESNI course took place in Barcelona, Spain, on 28 September
1 October, 2003. Each of the four days was organised as a major
immune-mediated pathology of diseases in the central and peripheral session on innate immunity and brain functions, neurodegeneration
nervous system.The final goal is to be able to prevent and/or treat and immunoregulation, relevance of autoandibody research in
these diseases, multiple sclerosis being the most prominent. The neuroimmunology, and immunotherapy in neuroimmunology.There
were 32 talks with speakers from 11 different countries.There were
European School of Neuroimmunology (ESNI) has been established
more than 250 participants, 95% from Europe, and 20% from eastern
to be a European framework for continuous educational programmes Europe.There were an equal number of female and male participants.
in neuroimmunology,and also to promote trans-national research co- Sixty travel grants were distributed, and nearly all participants from
eastern Europe were assisted in this way. One half of the participants
operation in the field. Yearly ESNI teaching courses have been a
were medical doctors, one half basic scientists. The course was
cornerstone to fulfil these aims. The objectives of the 4th ESNI organised with formal talks, informal discussion sessions, and
Teaching Course in Barcelona in September 2003 were to improve organised tables for lunch with the expert where the participants
both research and clinical practice through increased international co- could choose their mentor and discussion partner.A CD-ROM was
produced with the full scientific content from the teaching course.
operation and combine basic and clinical research groups working on This was distributed to all participants. Questionnaires with free text
translational projects. comments were returned from a majority of participants.The follow-
up work of the project has included planning of further ESNI teaching
courses, neuroimmunological research and education activities, and
Background joint projects within and outside the EU framework programmes.
Neuroimmunology is a rapidly expanding field aimed to define the
pathogenic mechanisms underlying immune-mediated disease of the
central and peripheral nervous system. The final goal is to define
targets to establish new and efficient therapeutic projects. The application of the results of this project should lead both to
Neuroimmunology is a translational field of research owing to its improved research in neuroimmunology and to better treatment,
ability to study molecular and cellular pathogenic mechanisms, to diagnosis and prevention of neuroimmunological disease.The course
establish animal models and to develop new therapeutic approaches. should foster international collaboration on high-quality projects and
Major neuroimmunological diseases are multiple sclerosis, give increased knowledge and skills to all participants.The ESNI work
myasthenia gravis, paraneoplastic disorders, encephalitis, myelitis, should also increase the interest and awareness of the challenges
Guillain-Barr syndrome and myositis. Disorders with within this field, and by this improve the framework for research and
neuroimmunological aspects are stroke, Alzheimers disease and optimal clinical practice for neuroimmunological diseases.
Parkinsons disease. Neuroimmunological diseases are therefore
major contributors to the burden of disease, loss of function,
disability and lost life years in Europe.
Aim
The aim of ESNI and of the 4th ESNI course is to foster high-quality
neuroimmunological research and collaboration throughout Europe.
This will also improve good clinical practice. Improved co-operation
between research groups in Europe, especially between
neuroimmunology, neurogenetics and neuro-proteomics, was also an
aim in integrating basic science and clinical topics in true translational
research. Further aims were to improve co-operation between
eastern and western Europe, and being aware of giving equal
opportunities to female and male research participants.The teaching
course should be a contact forum between senior and junior
researchers, between basic and clinical research, building a trans-
European network.

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Coordinator Prof. Graus, Francesc
Prof. Gilhus, Nils Erik Servicio de Nevrologia
Department of Neurology Hospital Clinic I Provincial
Haukeland University Hospital Barcelona, Spain
5021 Bergen, Norway Prof. Probert, Lesley
Phone: + 47 5597 5000 Laboratory of Molecular Genetics
Fax: + 47 5597 5165 Hellenic Pasteur Institute
E-mail: negl@helse-bergen.no Athens, Greece
Project web-site: www.esni.org Prof.Willison, Hugh
Key words: neuroimmunology, teaching course, neuro- Department of Neurology

science, multiple sclerosis Southern General Hospital
Glasgow, Scotland
Partners
Prof. Montalban, Xavier
Acronym: ESNI course 2003
Unitat de Nevroimmunologia Clinika Project number: LSSM-CT-2003-502993
Hospital Vall DHebron EC contribution: 50 000
Barcelona, Spain Duration: 10 months
Prof. Martino, Gianvito
Department of Biotechnology
San Raffaele Scientific Institute
Milan, Italy

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FENS Forum 2004 BRAIN, NEUROLOGICAL

AND PSYCHIATRIC
DISEASES
4th Forum of European Neuroscience
Summary Background
The 4th Forum of European Neuroscience, held in Lisbon on 10-14 The Federation of European Neuroscience Societies (FENS) is a
non-profit organization that includes over 15 000 European
July 2004, was one of the largest European meetings in the field of neuroscientists from all specialities in this field, affiliated in national
basic and clinical neuroscience.Topics addressed ranged from genes neuroscience societies from 24 European countries (Armenia,
and molecules implicated in brain function and dysfunction, to the Austria, Belgium, Czech Republic, Denmark, Finland, France,
Georgia, Germany, Greece, Hungary, Israel, Italy, Norway, Poland,
physiopathology and therapy of diseases such as major
Portugal, Romania, Russia, Spain, Sweden, Switzerland, The
neuropsychiatric and neurodegenerative disorders. A special Netherlands, Turkey, United Kingdom), as well as five
emphasis was given to translational science, i.e. how recent basic monodisciplinary multinational societies (the European Behavioural
Pharmacology Society, the European Brain and Behaviour Society,
scientific findings can rapidly and successfully contribute to
the European Society for Neurochemistry, the Federation of the
significant advances in the management of brain diseases with a high European Psychophysiology Society and the International
individual and socio-economic impact. Behavioural and Neural Genetics Society).
The Forum included nine plenary and 12 special lectures, 56 The FENS Council designated the Sociedade Portuguesa de Neuro-
ciencias (SPN) to organise the 4th Forum of European
symposia, seven technical workshops and approximately 3000 Neuroscience in Lisbon on July 10-14, 2004.The SPN is a non-profit
poster presentations from over 4500 participants. Two special scientific organization affiliated to FENS.
sessions took place, in association with the European DANA The FENS Forums of European Neuroscience are the largest
Alliance for the Brain, and with the European Brain Council. scientific meetings organized in Europe, and some of the largest in
the world, in the field of basic and clinical neuroscience, attracting
The main objectives of the Forum were: 1) to contribute to the most European neuroscientists, but also scientists from all over the
advance of neuroscience research, especially in Europe, by bringing world.The scientific programme of the Forum was established by
an independent international Scientific Programme Committee,
together experts from all over Europe and beyond, to present and
composed of senior scientists from different fields of neuroscience
discuss their latest findings with their peers; 2) to promote and from many European countries. The scientific programme
education in neurosciences, facilitating the participation of young covered topics ranging from basic neurobiology, e.g. genes and
researchers and PhD students, by providing specially reduced molecules implicated in normal brain functioning, but also in
numerous neurological and psychiatric dysfunctions, to the physio-
registration fees and stipends, and organizing one workshop on pathology and therapy of diseases such as epilepsy, Alzheimers
education in neuroscience in Europe; 3) to boost the collaboration disease or schizophrenia.
and scientific networks between European laboratories, including
eastern European countries, as stipends were available for both
young and senior scientists from those countries.
The Forum was particularly relevant to the objectives of the Specific

Programme Integrating and strengthening the European Research
Area, under the topic Specific brain research support actions. In
addition, it contributed to the objectives of establishing a European
Brain Research Area, as set out in a conference organised by the
European Commission on September 2003.

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Aim Potential applications

The main objectives of the FENS Forum of European Neuroscience The Forum represents a significant added-value to brain research in
were: Europe,as specialists from all European countries had the opportunity
to present to their peers their latest findings in virtually every field
1) to contribute to the advance of neuroscience research, specially
of the neurosciences. Neuroscientists from non-European countries
in Europe, by bringing together experts from all over Europe, as
also participated,further contributing to the advance of neurosciences
well as from other continents, to present and discuss with their
in Europe and elsewhere. A special session, co-organised with the
peers their latest findings;
European Brain Council, was held on Brain Research in Europe:
2) to promote education in neurosciences, facilitating the structuring European Neuroscience. New perspectives, as a follow-
participation of young researchers and PhD students, by up to the meeting organised by the European Commission on
providing specially reduced registration fees, grants and stipends, September 2003 on Brain Research in Europe.
and organizing one workshop on education in neuroscience in
Europe;
3) to boost the establishment of collaborations and scientific
networks between laboratories all over Europe, including eastern
European countries; special grants and stipends for participants
Coordinator
from those countries will also be available; Prof. Castro-Lopes, Jos
4) to raise public awareness of brain research by disseminating to Sociedade Portuguesa de Neurociencias
the general public the most relevant findings presented at the
Instituto de Histologia e Embriologia
Forum, and by promoting a special symposium on Public
Awareness of Brain Research. Faculdade de Medicina do Porto
By bringing together such a large number of European Alameda Hernani Monteiro
neuroscientists, with different personal perspectives and levels of
4200-319 Porto, Portugal
differentiation ranging from senior scientists to PhD students, an
additional objective was to provide the environment for informal Phone: + 351 225 091 468
discussions on topics relevant to the promotion of European
Fax: + 351 225 505728
neurosciences, such as the promotion of an European Brain
Research Area, the establishment of European Post-graduate E-mail: fens2004@med.up.pt
Neuroscience Programmes, the improvement of post-doctoral
Project web-site: www.fens2004.org
activities in Europe in order to avoid the brain drainage,
mechanisms for supporting post-docs working outside Europe to Key words: neuroscience, scientific meeting, Europe,
return to their own countries, etc. research
Expected results Partners

The abstracts of almost 3 000 scientific communications were Prof Mervyn Bibb
published in an abstract book (FENS Forum Abstracts, volume 2, 2004)
John Innes Centre, Norwich, United Kingdom
that is citable and covered by Current Contents,Medline and all major
indexing services. Abstracts are also available at the Forum website
and on CD. Therefore, the presented research findings were
disseminated to the entire scientific community, well beyond the
participants of the Forum. Acronym: FENS Forum 2004
A professional press office was in charge of spreading out to the EC contribution: 190 000
general public the most relevant findings presented at the Forum. Instrument: Specific Support Action
Duration: 15 months
Moreover, a special symposium was dedicated to Public Awareness Starting date: 01/01/2004
of Brain Research.

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Resource allocation to brain research in Europe
Summary Aim
In this project the costs of brain disorders in Europe are estimated and To investigate the funding resources for brain research in Europe and
assess the potential benefits and costs related to neuroscience of further
a next step is suggested: analysis of the funding of brain research efforts for brain research in Europe in the future. More specifically the
(neuroscience) in Europe. Both private funding and public funding will objectives of the study are to:
be analysed and divided into categories according to function or disease 1. analyse the resources used for brain research (neuroscience) in Europe
target.A comparison of the results will be made across countries within and to compare overall research efforts;
Europe, as with the USA and Japan. Furthermore, the project contains 2. compare the size and allocation of funding for neuroscience in Europe
an assessment of the potential benefits of further funding efforts for with resources used in the USA;
neuroscience in Europe in relation to costs.Several methods for testing 3. assess the potential benefits in relation to costs of further efforts for
this will be used, and results from a another project on the economic brain research in Europe through several tests:
burden of brain diseases in Europe will be used for comparison.The a. relating the total current funding for brain research in Europe with the
results from the assessments shall be compared with studies performed total economic burden of brain diseases in Europe
in other research areas and indicate the best possible use of funding b. assessing the value of brain research to health improvement and life
expectancy in Europe
allocation for research in Europe in future.These kinds of studies are
missing in Europe, and hence this project shall be a pioneer in an area c. assessing the cost-effectiveness of further funding for brain research in
Europe
receiving more and more attention in the research community as well
4. disseminating the above results to clinical and basic scientists,patients,
as in policy discussions in the European setting.
politicians, other decision-makers and to people of Europe.
Background Expected results

Brain research has not been sufficiently high on the European agenda.
The project will result in the best possible estimates of public and
The spending on brain research in Europe is much lower than similar
private research spending for brain diseases in Europe, as well as
spending in the United States or Japan, and is not commensurate with
provide an estimate of the economic benefits for Europe from
the burden of these diseases or to the importance of understanding
previous advances in brain research, and an estimate of the potential
the normal brain. It is generally accepted that Europe led in brain
benefits from further investments in different areas of brain research.
research until approximately 10 or 20 years ago. At that time this
The RABRE project will provide a framework for assessing the value
role was taken over by the United States and the gap between
for society of medical research in general and brain research in
European brain research and United States brain research continues
particular, and set the stage for a discussion about priorities to and
to widen. A similar consideration is true for Japan although this
within brain research (neuroscience).
country produces a considerably lower quantity of brain research.
Brain research is extremely important for the biotech industry, and
drugs for brain diseases together represent the biggest single future Potential applications
indication for drugs.The present project will contribute to increase
understanding of the importance of new treatments for brain diseases The results will be directly useful for legislators and administrators
and, hopefully, via stimulating the interest in brain research and via concerned with priorities for investments in life sciences and
increased and focused (and efficient) funding for brain research will biotechnology for health.Moreover,it is expected that the results of the
help to increase European competitiveness in this field. present study will be important for policy development both at European
level as well as at national level in Europe.The results from the project
will provide solid information on the value of further research in
neuroscience in Europe. Hence, it is anticipated that the results shall be
a basis for decision-makers in the political and scientific communities in
Europe.

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Coordinator
Prof. Olesen, Jes
European Brain Council
Glostrup Hospital
Nordre Ringvej
2600 Glostrup
Copenhagen, Denmark
Phone: + 45 43 23 30 36
Fax: + 45 43 23 39 26
E-mail: jeol@glostruphosp.kbhamt.dk
Project web-site: www.ebc-eurobrain.net
Key words: brain disorder, brain disease, neuroscience,
health economics, economics, epidemiology,
funding, cost-benefit, cost-effectiveness,
Europe
Partners
Prof. Jnsson, Bengt
Stockholm Health Economics
Stockholm, Sweden
Acronym: RABRE
Duration: 18 months

140
Human
development
and ageing
MIMAGE 142
GEHA 144
EMBIC 146
Cells into Organs 148
LINK-AGE 150
ANABONOS 152
OSTEOGENE 154
AGEACTION 156
HUMAN DEVELOPMENT MIMAGE

AND AGEING
Role of mitochondria in conserved

mechanisms of ageing
Summary war of the generations is expected.A solution will only be possible
by an integrated approach: political decisions (e.g. restructuring social
The overall aim of this programme is to assess the role of and health insurance systems) and substantial scientific advances to
understand the basics of biological ageing and to use this
mitochondrial function in ageing and lifespan control.The strategy used
understanding to intervene in the processes of ageing.
is to discover mechanisms that show evolutionary conservation
Unfortunately, although in the last three decades more information
between invertebrate and mammalian model systems.A unique matrix about the molecular mechanisms of ageing have been established, in
of model organisms (yeast, Podospora anserina, Caenorhabditis elegans, not one biological system are these mechanisms sufficiently
Drosophila melanogaster, mouse and rat) and cell culture systems is understood in detail. However, it is generally accepted that major
conserved or public mechanisms exist in addition to mechanisms
used. Specific questions will be experimentally tested.The following
which are species-specific or private. Unravelling the public
age-related issues are addressed: (i) modulation of mitochondrial mechanisms of ageing is thought to be of special importance because
reactive oxygen species (ROS) by different means, (ii) relevance of these seem to be the mechanisms of general relevance. Our strategy
is to elucidate these mechanisms in various biological systems.At the
molecular and cellular pathways to maintain a healthy population of
organism level, the two fungi Saccharomyces cerevisiae (yeast) and
mitochondria, (iii) nature and impact of signalling pathways on Podospora anserina, the nematode Caenorhabditis elegans, Drosophila
mitochondrial activity, (iv) effects of dietary restriction on melanogaster, mice and rats offer important advantages for
mitochondrial activity, (v) novel age-related mitochondrial functions. experimental research (e.g.short life-time,accessibility to genetic and
molecular analysis) and therefore are preferred ageing models. In
The participating laboratories have a strong commitment for addition, cell cultures are investigated extensively.
collaborative work and ideally complement each other. Some of the
partners extensively collaborated in the past or are collaborating Aim
presently in the field of research addressed in this IP. They are working
The specific aim of this project is to unravel the molecular conserved
with different model organisms and systems, most are well mechanisms of normal or healthy ageing. The strategy is to use a
experienced in the field of experimental biogerontology,and they each variety of systems with a special emphasis on organismic ageing.These
have a specific expertise in different fields of research ranging from models are clearly independent complete organisms with a long
history of evolution, but are much less complex in their organisation
advanced biochemistry, cytology, genetics to molecular biology.This than humans. The consortium, however, does include sub-projects
consortium is in the unique situation of performing competitive studying cell culture systems as well. As well as different cell cultures
research with other programmes aimed at identifying and from normal subjects one important premature ageing model,
Cockayne Syndrome, is included.The consortium covers a variety of
characterising mechanisms of ageing that are conserved in most
ageing models,a prerequisite for the identification and characterisation
species, hence called 'public' mechanisms of ageing. At the same time, of public ageing mechanisms. A very important advantage of the
the IP complements European activities that follow other strategies selected systems is that they are accessible to experimentation.
Therefore, specific questions can be asked and, due to the short life-
(e.g., comparing mitochondrial parameters from human tissues of
span of some of the systems, can be addressed experimentally in a
different human populations) to elucidate the role of mitochondria way that is not possible in higher organisms like humans. Moreover,
in human ageing. a variety of long-lived mutants are available. The analysis of these
mutants has contributed and will continue to contribute significantly
to what is known about basic molecular pathways governing ageing.
Problem The consortium is in the situation of being able to go considerably
Ageing as the progressive loss of function and consequently an beyond those investigations which in the past has generated a huge
increase in morbidity is a serious social problem.Today, social security body of essentially correlative data.
and health insurance systems are collapsing. Almost every day new
strategies to safeguard these systems (e.g. by increasing the rates to
be paid by the individual) are discussed in politics and large parts of
the European population are fear that their pensions will be lost in
the near future.With an increasing proportion of the elderly in the
population in the next decades this problem will keep growing and a

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HUMAN DEVELOPMENT
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Expected results
1.The establishment of efficient procedures for the isolation of
Coordinator
coupled mitochondria in Podospora anserina and Caenorhabditis Prof. Osiewacz, Heinz D
elegans.
Botanical Institute, Johann Wolfgang Goethe-University
2.The establishment of procedures for efficient measuring of reactive
Marie-Curie-Str. 9
oxygene species in Podospora anserina and Caenorhabditis elegans
60439 Frankfurt, Germany
3.The establishment of procedures for the efficient identification of
oxidatively damaged proteins and for monitoring mitochondrial lipid Phone: + 49 69 798 29264
peroxidation.
Fax: + 49 69 798 29363
4. Identication and definition of the impact of exogenous and
E-mail: osiewacz@em.uni-frankfurt.de
endogenous factors/ components (e.g. uncoupling proteins,
nutrition) which affect oxidative stress on mitochondrial functions Project web-site: to be created
and ageing.
Key words: ageing, mitochondria, model systems, reac-
5. Determination and characterisation of specific mitochondrial tive oxygen species, molecular mechanisms
functions (mtDNA stability, mtDNA repair, heat shock proteins,
turnover of mitochondria) affecting lifespan and ageing.
Partners
6. Demonstration that and how different signaling pathways
(retrograde signalling, cAMP/PKA, and insulin/IG1 signalling) affect Zoological Institute, Johann Wolfgang Goethe-University,
mitochondrial functions. Frankfurt, Germany
7. Identification and characterisation of additional (novel) age-related Institute of Genetics, University of Salzburg, Austria
mitochondrial functions causatively linked to ageing. Faculty of Chemistry, Physical Biochemistry,Technische
Universitt Darmstadt, Germany
Potential applications Laboratory of Genetics,Wageningen University,The
Netherlands
The general knowledge generated in this project may in the future
be used to develop specific interventions into the ageing process of Institute for Biomedical Aging Research, Austrian
biological systems. Academy of Sciences. Innsbruck, Austria
Acronym: MIMAGE
Duration: 60 months

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HUMAN DEVELOPMENT GEHA

AND AGEING
GEnetics of Healthy Ageing

Summary can be found by studying the selected group that survives past age
90. A network of geriatricians, demographers, geneticists and
GEHA will identify genes involved in healthy ageing and longevity, statisticians is involved in GEHA to investigate the genetic basis of
the ageing process in humans.
which allow individuals to survive to advanced old age in good
cognitive and physical function and in the absence of major age- It is predicted that in addition to new information on the genes
governing healthy ageing, innovative bioinformatic algorithms,
related diseases.The work plan is: demographic/mathematical models and powerful statistical
approaches will be developed as a result of GEHA.
(i) to collect 2800 long-lived (90+) sibpairs and 2800 unrelated
younger control subjects from ten European countries and
China;
Aim
Major goals of GEHA project are:
(ii) to perform a genome scan in all the sibpairs (Affected SibPair
1. to recruit 2800 long-lived sibpairs and 2800 younger control
Analysis, ASP) in order to identify new chromosomal regions
subjects from 17 geographic areas for genome scanning in order
harbouring putative longevity genes, followed by positional to identify chromosomal regions involved in longevity and healthy
cloning and mutational analysis and preceded by LD block ageing;
structure in CEPH families; 2. to perform bioinformatic,functional genomics and proteomics and
molecular biology studies on the longevity regions/genes and gene
(iii) to thoroughly investigate in cases and controls three candidate variants resulting from ASP analysis and Linkage Disequilibrium
regions in chromosomes 4, 11 and 19 that according to previous (LD) mapping;
studies are involved in ageing and longevity; 3. to test whether ethnically different populations share the same
genes involved in ageing and longevity;
(iv) all the recruited people will be genotyped for mitochondrial
DNA haplogroups and C150T mutation known to play a major 4. to verify if the genes involved in longevity and healthy ageing in
the European population are the same in an ethnically different
role in ageing and longevity. population such as the Chinese;
Gender-specific genes involved in healthy ageing and longevity in 5. to ascertain the role played in human longevity by three candidate
women and men stratified for ethnic and geographic origin and regions;
APOE genotype will be identified; a longitudinal survival study to 6. to verify in different populations the role of mtDNA haplogroups
assess the impact of the identified genetic loci on 90+ people as putative genes affecting longevity, and to study their interaction
with the newly emerging longevity nuclear genes;
mortality will be performed; mathematical and statistical models
capable of combining genetic data with demographic characteristics, 7. to identify gender-specific genes differently involved in healthy
ageing;
health status, socio-economic factors, lifestyle habit will be
8. to stratify the sample according to APOE genotype, the only
developed.
genetic marker which so far has been found to be associated with
reduced longevity in a variety of populations;
Problem 9. to develop innovative analytical strategies capable of combining

all the data collected (clinical,socio-economical,related to lifestyle,
In 2000, 69 million people worldwide were aged 80 or over. This demographic and genetic);
population is the fastest-growing segment of the population. By 2050
the 80+ years old group is expected to increase five-fold to 377 million 10. to evaluate the importance of genetic factors on the mortality of
and represent 4.4% of the population.The number of nonagenarians the recruited sibpairs.
will reach 63 million by 2050, which is an eight-fold increase.
Centenarians currently estimated at 167 000 will reach a projected Expected results
5.3 million worldwide. Europe is the area where population ageing is
most advanced. This demographic explosion makes it critically The project should help in identifying biological and non-biological
important to identify the factors involved in ageing devoid of major determinants of successful/unsuccessful ageing and longevity, and in
diseases and disabilities, contributing to increase the number of old particular genes and gene variants as new and innovative targets for
European citizens in good health.Clues concerning such healthy ageing diagnostic and therapeutic strategies of age-related pathologies and

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HUMAN DEVELOPMENT
AND AGEING
disabilities. These findings will represent a starting point for new

activities to be developed and exploited by the European biotech Coordinator
companies which are part of the GEHA consortium. The following
outcomes are expected: Prof. Franceschi, Claudio
- development of ad hoc protocols, standardised at European scale, University of Bologna - CIG
for the assessment of the health status of the oldest old;
Via Zamboni 33
- development of new ad hoc algorithms capable of combining clinical,
40126 Bologna, Italy
social and genetic data in order to identify subgroups of old people
at higher risk for the development of age-related diseases/disabilities; Phone: + 39 051 2094743
- development of ad hoc microarrays for the assessment of Fax: + 39 051 2094747
successful/unsuccessful healthy ageing;
E-mail claudio.franceschi@unibo.it
- development of molecular biology methods capable of exploiting the
Project web-site: http://www.geha.unibo.it
knowledge related to the genes associated with healthy ageing and
longevity to counteract the activity of genes related to major age- Key words: healthy ageing, longevity, demography, affect-
related diseases and disabilities. ed sibpair analysis, linkage disequilibrium
mapping, mitochondrial DNA, APOE, func-
tional genomics, proteomics, gender, genetic
Potential applications ethical issue
The genetic approach of GEHA, combining ASP analysis and LD
mapping,is applied to a very large number of 90+ sib pairs and younger Partners
control subjects newly recruited across Europe. This experimental
2 France
design will allow:
2 Germany
(i) an independent genetic mapping of any chromosomal areas of
special interest; 6 Italy
(ii) a comparison between Sardinia (with its unusual enrichment of 1 The Netherlands
male centenarians) and Finland (with their unique genetic
1 Greece
characteristics) with other European countries;
2 Finland
(iii) a comparison of the data obtained on the genetics of longevity
within European populations to those obtained by the Beijing 1 Poland
Genomics Institute (BGI) on a large collection of DNA and clinical
2 United Kingdom
data regarding a totally different ethnic group such as the Han
Chinese population; 3 Belgium
(iv) subgroup comparisons with respect to social and environmental 2 Denmark
factors.
1 Peoples Republic of China
Acronym: GEHA
Duration: 60 months

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HUMAN DEVELOPMENT EMBIC

AND AGEING
The control of embryo implantation. Studies of gene

expression, protein profiles / functions at the utero
embryonic level: Cellular and molecular developmental
events at the fetomaternal interface
Summary At present, fragmentation of experimental capacity and disparate
approaches result in lack of a comprehensive skills base, and lack of
Understanding the cause of female infertility, as well as the molecular access to very specialised approaches and technological platforms
such as animal experimentation in very strict conditions, genomics
mechanisms of embryo implantation, is important for treating the
and proteomics facilities or multicentric clinical evaluation. These
former and increasing the success rate of IVF- ET. Discrete molecular require being used in a coordinated fashion to maximise their effect
implantation defects might also be the primary lesion in pre-eclampsia. in this area.
EMBIC will network and structure leading but unlinked European groups We will thus:
so as to catalyse their efforts and maximise their potential. Recent 1. assemble critical talents and approaches, to develop an
advances in genomics and proteomics open the possibility of integrative, evaluative, capacity to set up EMBIC;
understanding what recent KO animal studies and clinical evidence 2. integrate EMBIC laboratories using crucial models and
highlight as being the main events controlling implantation. coordination of the joint programme of activities:
2.1. early embryo signalling to ultimately allow selection of only those
Problem embryos which will effectively implant;
2.2. key events in tissue remodelling;
Female sterility is increasing in Europe and this is partly countered by
Assisted Reproductive Technologies. In December 2002, the European 2.3. homing/ proper activation of Natural Killer (NK) cells;
in Vitro Fertilisation (IVF) Embryo Transfer (ET) monitoring programme
2.4. role of MHC class I gene products and their recognition by NK
reported in a study from 22 countries some 258 460 cycles of treatment.
cells;
The success rate is stalled at present around 25% for IVF and 27% for
ICSI (intra cytoplasmic sperm injection).As a partial consequence of the 2.5. control of the inflammation complement related pathways;
rise in infertility, compared with 1998, the number of cycles increased
2.6. cytokine/ chemokines/ profiling;
by 11%, and projections are for a similar increase in the 2003-2004
period. Understanding the cause of such a rise in female infertility is
therefore of prime importance. Furthermore, the success rate of ET
remains low, which is costly psychologically and financially. In most
European member countries,a single cycle costs of the order of 3 000
to 5 000.In addition,as an empirical approach to improve implantation
rates,several embryos may be transferred,normally resulting in a multiple
pregnancy and delivery rate of 26.3% (most often,but not always,twins). A murine pre
Finally, discrete molecular implantation defects might be the primary implantation
lesion in pre-eclampsia, a high risk disease frequent in Europe and the uterus labelling
major cause of maternal mortality (1.5 deaths /100 000 pregnancies), with DBA lectin
causing many associated maternal deaths in developing countries.Limiting
reveals it is com-
factors to implantation seem to be the implantation window, the
posed at 80%
proper formation of a functional decidua basalis with intensive tissue
of activated
remodelling (uterus), and de novo organogenesis (placenta
lymphocytes of
formation).
the natural killer
cells lineage
Aim
We aim to build an European virtual laboratory on major
mechanisms of implantation by thoroughly exploring what knock
out mice have recently established as cellular-cytokine networks/ key
pathways promoting the development of two de novo organs: the
decidua basalis and the mature placenta.

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HUMAN DEVELOPMENT
AND AGEING
2.7. invasion and early post-implantation events, Matrix Metallo

Protease (MMP) based proteolysis/ adhesion molecule Coordinator
functions.
Dr Chaouat, Grard
3. constitute a European cohort of infertile women with creation of RT
Unit 131 INSERM
generated DNA, sera and micro-biopsy tissue samples banks;
Equipe cytokines et relation materno foetale
4. establish guidelines for management of infertile women combined
with diagnosis procedures and ultimately recombinant technologies Maternit Hpital Antoine Bclre
therapies for selected pathologies;
92141 Clamart CEDEX, France
5. open the network of validated platforms for education and
Phone: + 33 14 537 4450
cooperative experimentation.
Fax: +33 14 537 4450
EMBIC will contribute and benefit from the creation of integrated
platforms based on animal models, genomic and proteomic facilities, E-mail: gerard_chaouat@wanadoo.fr
protein intra-net database set-up and integrated clinical set-up.EMBIC
Project web-site: www.embic.org
will spread excellence by facilitating the exchange of scientists within
the laboratories, promote recruitment/training of out-network post- Key words: embryo, implantation, signals, HLA-G, NKs,
docs, organise workshops and satellite meetings in pan-European or inflammation, complement, arteries, spiral
regional immunology/fertility meetings and an annual summer school.
Partners
Expected results
4 France
We believe that we will answer the following questions:
2 United Kingdom
1) Which preimplantation embryo signals permit only some embryos
1 Spain
to implant in a receptive uterus?
4 Italy
2) Why is there such a high proportion of NK cells in the implantation
uterus, a percentage higher even than that seen in lymph nodes? 2 Hungary
3) What is their origin? 2 Germany
4) Which embryonic cell surface soluble factors signals induce the 1 Belgium
proper NK activation vs. an abortogenic one?
1 Austria
5) What are the cellular and molecular determinants of a tolerant
uterus?
Acronym: EMBIC
6) Which molecules/cells control early stroma remodelling and tissue Project number: LSHM-CT-2004-512040
differentiation (particularly spiral arteries)? EC contribution: 7 400 000
7) What controls trophoblast invasion and differentiation? Duration: 48 months
8) Which uterine growth factors permit proper placental dif-
ferentiation (essentially at trophoblast level) and growth?
Screening of the embryos to determine those which will implant,
improvement of IVF ET success rate,determination of new strategies
for IVF-ET management, identification of genetic defects in sterility,
understanding local uterine angiogenesis,insights into the mechanisms
of pre-eclampsia. It is also expected that we will identify new gene
expression defects causing female sterility as well as define therapeutic
approaches and diagnostic tools.

147
HUMAN DEVELOPMENT Cells into Organs

AND AGEING
Cells into organs: Functional genomics for development

and disease of mesodermal organ systems
Summary strategies are redeployed, not only at different sites during
embryogenesis, but also during later tissue regeneration, is essential
This network will elucidate molecular and cellular processes underlying for understanding and eventually correcting,by appropriately targeted
therapeutics,any malformation or deregulation which affects the adult
specification and differentiation of mesodermally derived organ systems.
organ and is the basic knowledge required for organ and tissue
We integrate developmental genetics and experimental embryology engineering.It will enable identification of the gene cascades associated
with modern cell biology and genome scale analysis. These new with deadly or disabling genetic diseases and of suitable target genes
for drug discovery.It will point the way for making specifically tailored
technologies will enable us to identify genes which function in building
stem cells for a multitude of therapeutic applications and for organ
a specific organ or in a particular aspect of embryogenesis. A major development in vitro.
revelation of developmental biology has been the extent to which
molecular strategies are redeployed,even during regeneration.Thus this Expected results
information is the basic knowledge required for organ and tissue
- We will sustainably integrate the participating groups into a durable
engineering. world force in this area.
- We integrate users and facilities into the networks Joint Technology
Problem Platform.
The development of new approaches to treating disease will - We develop a Joint Programme of Research which will generate
revolutionise health care in the coming decade.Treatment of cancers important publications and joint initiatives during the networks
will increasingly rely on targeted molecules rather than cytotoxic lifetime
drugs. Manipulation of stem cells for cell and tissue replacement
- We organise a series of network symposia and a series of summer
therapies holds great promise for treatment of degenerative disease
schools.
and injury. Both approaches depend critically on detailed knowledge
of the molecular and cellular events governing normal differentiation - At least 20 completed PhDs will emerge from the network over its
of the target organs and tissues. This knowledge provides the basis lifetime, as will a number of new independent groups.
for organ and tissue engineering.
- We expect the network to generate industrial applications/ patents
Many important diseases affect organ systems such as heart, as saleable technology.
vascular system, blood, kidneys, skeleton, and musculature - deriving
substantially or exclusively from mesodermal cells. Heart failure and
strokes resulting from atherosclerosis, kidney failure, muscular Potential applications
dystrophy, osteoporosis, tumours and leukaemia are caused either Genomic and postgenomic approaches will be applied to understand
by defects in development of these mesoderm containing organ human development and ageing.This will develop the evidence base
systems or in their function, frequently as a consequence of ageing. for improving public health strategies to promote healthy
Together, these diseases represent principal obstacles to reaching a development and ageing.
healthy old age.
Aim
The aim of this network is to integrate the established methodologies
of developmental genetics and experimental embryology with the
sophisticated approaches of modern cell biology and the new
methodologies of genome scale analysis made possible by genome
sequencing projects.These new technologies will enable us to identify
many of the genes which function in building a specific organ system
or in directing a particular aspect of embryogenesis.Analysing these
genes,investigating their functions,and placing them in developmental
cascades as well as following the cells which they affect, will
undoubtedly reveal new aspects of organ development,extending and
completing the existing picture. The extent to which molecular

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HUMAN DEVELOPMENT
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Coordinator Dr Jacinto, A, Dr Thorsteinsdottir, Solveig, Dr

Palmeirim, Isabel and Dr Rodrguez-Len, Joaqun
Dr Durston, Anthony J.
Instituto Gulbenkian de Ciencia/Fundacao Calouste
The Netherlands Institute for Developmental Biology Gulbenkian
Uppsalalaan 8 Oeiras, Portugal
3584 CT Utrecht,The Netherlands Dr Jaeckle, Herbert
Phone: + 31 30 212 1800 Max-Planck-Gesellschaft zur Foerderung der
Fax: + 31 30 251 6652 Wissenschaften e.V.
E-mail: tony@niob.knaw.nl Max Planck Institute for Biophysical Chemistry
Project web-site: www.cellsintoorgans.net Gttingen, Germany
Key words: organogenesis, stem cells, mesodermal Dr Wagner, Erwin and Dr Hartmann, Christine
organs Forschungsinstitut fur Molekulare Pathologie Ges. M.b.H.
Research Institute of Molecular Pathology
Partners Vienna, Austria
Dr Deschamps, Jacqueline and Dr Korswagen, Rik
Dr Affolter, Markus and Dr Gehring,Walter
The Netherlands Institute for Developmental Biology
University of Basel
Basel, Switzerland
Dr Grosveld, F, Dr Dzierzak, Elaine and Charit,
Dr Duboule, Denis
Jeroen
University of Geneva
Erasmus University Medical Centre
Department of Zoology and Animal Biology
Rotterdam,The Netherlands
Geneva, Switzerland
Dr Gurdon, John and Dr Smith, Jim
The Wellcome Trust/Cancer Research United Kingdom
Gurdon Institute of Cancer and Developmental Biology Acronym: Cells into Organs
Cambridge, United Kingdom EC contribution: 7 200 000
Dr Ingham, PW, Dr Borycki,Anne-Gaelle and Dr Duration: 60 months
Roehl, Henry Starting date: 01/04/2004
The University of Sheffield
Sheffield,, United Kingdom
Dr Stern, C and Dr Wolpert, Lewis
Dr Buckingham, Margaret and Dr Nicolas, Jean-
Franois
Institute Pasteur
Paris, France
Dr Cossu, Giulio
Fondazione Centro San Raffaele Del Monte Tabor,
Milan, Italy

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HUMAN DEVELOPMENT LINK-AGE

AND AGEING
Coordination and consolidation of European

Biogerontology: en route towards formation
of a European College of Biogerontology
Summary the underpinning science of biological ageing, in order that it shall
be possible to minimise dependency and improve quality of
Coordination and Consolidation of European Biogerontology will life for the rapidly growing numbers of older people.
represent a step forward en route towards the formation of a Recent advances indicate that it is possible to intervene positively in
European College of Biogerontology. LINK-AGE will be a the mechanisms that cause age-related frailty, disability and disease,
particularly by developing and exploiting the fields of genomics and
Coordination Action building upon, and very significantly extending, biotechnology for health in old age.These fundamental advances in
existing European research in this field. Such research is still science and technology offer exciting opportunities to extend health
fragmented,limiting the ability to progress in an area of great economic span (period of good quality life and functional \independence) and
to develop European industry addressing the challenges of age.
and social importance for the future of Europe.
At present, European research capacity in biogerontology is still
LINK-AGE will provide an open, transparent mechanism to integrate fragmented although efforts have been made through the
research by addressing the following core objectives: Integrated Project programme of the European Union. This limits
ability to make progress and results from several causes. First, the
1) To identify common research strategies that will generate critical biology of ageing is itself inherently complex,with targets for study
mass and added-value from European biogerontology research. at many levels from molecules to cells to tissues to whole organisms,
and in many different biomedical contexts (e.g. dementia,
2) To establish a process that will help bring new researchers into the osteoporosis, visual impairment, declining immune function, etc).
field from new geographical regions within the wider European Second, in view of the practical advantages of working with short-
lived model organisms, research is currently being conducted on a
community.
wide range of species (fungi, invertebrates, rodents, other ma-
3) To establish a process that will bring new researchers into the field mmals, birds) as well as humans.
from other research areas within life sciences and health of Biogerontology intrinsically requires integration of research across
relevance to ageing and longevity. different biological levels, species, and biomedical contexts (e.g. it is
likely that some of the same fundamental mechanisms are shared).
4) To establish a framework that will allow effective integration of Therefore there is need for a new coordination action that aims:
research on different species to maximise the opportunities for (i) to achieve stronger integration and effectiveness within the field;
synergy and interaction between researchers working on such species. (ii) to develop links between basic research and industry, particularly
to help stimulate the success of existing SME's or new SMEs;
To meet these objectives, LINK-AGE will support a closely
coordinated programme of topic working groups, workshops and (iii) to include and to support the participation of scientists across
the full geographical span within Europe, particularly including
conferences, summer schools, and dissemination activities. Through scientists from candidate and associate states of the EU.
its dissemination activities,it will develop effective links with the wider
public and industry, in order that translation into benefit of emerging Aim
knowledge of the underpinning science of healthy ageing can be
Scientific coordination
exploited as rapidly as possible.
The objectives of LINK-AGE in terms of scientific coordination are:
Problem a) To identify and help implement common research strategies that

will generate critical mass and added-value from European
Europe faces the immense challenge of unprecedented increase in biogerontology research.
life expectancy, which will continue into the 21st century.Although
b) To establish a process that will help bring new researchers into the
this state of affairs is the essentially positive outcome from multiple
field from new geographical regions within the wider European
improvements in health care and socioeconomic circumstances, it
nevertheless presents great strains for all member and associated community.
states of the European Union in terms of increasing prevalence of c) To establish a process that will bring new researchers into the field
age-related health problems and the growing financial implications from other research areas within life sciences and health of
for pensions, etc.There is urgent need for more basic research on relevance to ageing and longevity.

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HUMAN DEVELOPMENT
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d) To establish a framework that will allow effective integration of

research on different species to maximise the opportunities for Coordinator
synergy and interaction between researchers working on such species.
Dr.Toussaint, Olivier
Technical coordination FNRS Research Associate
The objectives of LINK-AGE in terms of technical coordination are: University of Namur (FUNDP)
a) To establish a category of associate membership of LINK-AGE for Research Unit on Cellular Biology (URBC)
those wishing to make connections with the field, but whose work Rue de Bruxelles, 61
does not yet meet the criteria for quality and relevance. B-5000 Namur, Belgium
b) To use the membership structure to draw into the membership of Phone: + 32 81 724132
LINK-AGE researchers from diverse geographical regions within Fax: + 32 81 724135
Europe, particularly those previously disadvantaged in access to E-mail: olivier.toussaint@fundp.ac.be
scientific research support.
http://www.fundp.ac.be/urbc
c) To develop and support a series of LINK-AGE, conferences, and
summer courses to address the scientific objectives.
Partners
d) To establish an organizational framework for LINK-AGE to meet
Prof.TBL Kirkwood
its scientific and technical objectives and to validate the concept
of a distributed network of excellence in biogerontology research University of Newcastle upon Tyne, U.K.
across Europe. Prof. M. Blasco
Spanish National Cancer Centre, Spain
Potential impact Dr. G. Butler-Browne
Universit Pierre et Marie Curie, France
Research that can lead to novel intervention to extend the health
span and improve quality of life at older age has the potential for Dr. ES Gonos
enormous impact in an ever-ageing society. Furthermore, the National Hellenic Research Foundation, Greece
growing anxiety and fiscal threat posed by increased pension costs Prof. E. Slagboom
is founded on biodemographic models of ageing that urgently need Leiden University Medical Center,The Netherlands
updating by better informed knowledge of the ageing process and
projections for future life expectancy. The scientific impact of the Prof. J.Vanfleteren
project will come from integrating the currently fragmented research University of Gent, Belgium
activity within Europe.The diversity of European research traditions Prof. R. Contreras
is potentially a rich resource for a topic as multi-faceted as Flanders Interuniversity Institute for Biotechnology, Belgium
biogerontology, but only if these diverse elements communicate with
Prof.T. Nystrom
each other and develop ways of working together.
University of Gteborg, Sweden
It is only recently that researchers in other fields of biomedical
Prof. CC Zouboulis
research related to middle and late life degenerative conditions (e.g.
dementia, cancer, cutaneous biology) have begun to recognise that Charite Universitaetsmedizin, Germany
since age tends to be the single biggest risk factor for the condition Prof. HD Osiewacz
they are studying, understanding why the aged cell or organ is more Johann Wolfgang Goethe-Universitt,Germany
vulnerable to pathology is likely to enable major breakthroughs.
Dr. M Salmon
LINK-AGE will impact on this hitherto under-recognised need by
encouraging many more researchers to participate in coordinated Straticell Screening Technologies, Belgium
work that connects the study of age-related conditions with the Prof. C. Franceschi
underpinning mechanisms of ageing. University of Bologna, Italy
It is now clear that ageing itself is the result of progressive, lifelong Prof BFC Clark
accumulation of a variety of molecular and cellular damage. This University of Aarhus, Denmark
implies that ageing is a process that operates cumulatively across
the life course and therefore events that happen at any age, even in
utero, can have a major impact on an individual's expectation of Acronym: LINK-AGE
length of life and of health in old age. LINK-AGE will encourage more Project number: LSHM-CT-2005-513866
researchers to address the links between early and late-life EC contribution: 1 100 000
processes.
Duration: 48 months

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HUMAN DEVELOPMENT ANABONOS

AND AGEING
Molecular Mechanisms of Bone Formation

and Anabolism
Summary Aim
Drug treatments which enhance bone formation are likely to be more The aim of the project is to gain better understanding of the
mechanisms by which bone formation is regulated with the aim of
effective than antiresorptive treatments in the treatment of patients identifying new molecular targets that will form the focus for new
with established osteoporosis.With this in mind, the present project therapeutic strategies for the management of osteoporosis.This will
aims to advance understanding of the mechanisms responsible for bone be achieved by investigating the transcriptional regulation of key target
genes that play a role in regulating bone formation; by defining the
formation, with the long-term aim of harnessing this knowledge to
effector molecules that are transcriptionally regulated by drugs and
develop new anabolic agents for osteoporosis. We will define endogenous signaling factors that stimulate osteoblast activity and by
downstream effectors of molecules that regulate bone formation in defining the signalling pathways that are activated in human genetic
diseases characterised by increased bone formation.Novel genes that
experimental models and identify the signalling pathways that are
regulate bone formation will be identified by positional cloning studies
activated in human genetic diseases characterised by increased bone in experimental models which show a bone phenotype as the result
formation. The mechanisms of action of drugs with known anabolic of ENU mutagenesis.
effects will be investigated and novel genes that regulate bone formation
will be uncovered by ENU mutagenesis and genetic mapping studies. Expected results
The project will lead to a greater understanding of how bone formation 1. Better understanding of the mechanisms by which genes that
is regulated and will underpin the development of new therapeutic promote bone formation are regulated at a transcriptional level.
strategies for the prevention and treatment of osteoporosis. 2. Identification of a common set of target genes that are regulated
by potentially anabolic drugs and endogenous factors that promote
bone formation.
Problem
3. Generation of experimental models that will provide proof of
Osteoporosis represents a major disease burden in Europe and occurs
concept that genetic manipulation of putative anabolic molecules
because there is relative uncoupling between the amount of bone
can promote bone formation in vivo.
removed by osteoclastic bone resorption and that which is replaced
by new bone formation. Most of the drugs that are used to treat 4. Identification of novel genes that regulate bone formation by
osteoporosis act by inhibiting bone resorption and there is only one classical positional cloning studies.
treatment available (the 1-34 fragment of parathyroid hormone) that
works by stimulating bone formation. Antiresorptive therapies are
highly effective agents for the prevention of osteoporosis, and also
reduce the risk of fracture in patients with established osteoporosis. The molecules and target genes that are identified by this project will
They work less well in patients with more advanced disease,however, represent a new generation of molecular targets that can potentially
because they are incapable of replacing bone tissue that has been lost act as anabolic drugs themselves, or can act as targets for the design
as the result of the osteoporosis. of new drugs that enhance bone formation.The project will therefore
be of value in helping to develop new treatments for osteoporosis
with associated benefits for citizens who suffer from this disabling
disease, in the European Community and beyond. It is also anticipated
that new intellectual property will be developed during the project
which could have positive implications for generating income for the
higher educational institutions and commercial companies that are
taking part in this project.

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HUMAN DEVELOPMENT
AND AGEING
Coordinator
Prof. Stuart, H Ralston MR FRCP FmedSci Dr Garcia,Teresa
ARC Professor of Rheumatology Proskelia Pharmaceuticals
Rheumatic Diseases Unit Romainville
University of Edinburgh Paris, France
Western General Hospital Dr Grigoriadis, Agi
Edinburgh EH2 2XU, United Kingdom Department of Craniofacial Development
Phone: +44 131 537 1088 Kings College London
Fax: +44 7714 266 616 Guys Hospital
E-mail: stuart.ralston@ed.ac.uk London, United Kingdom
Project web-site: http://www.abdn.ac.uk/anabonos Dr Gannon, Frank
Key words: osteoporosis, bone formation, anabolic, EMBL Heidelberg
parathyroid hormone, osteoblast
Heidelberg, Germany
Dr Wagner, Erwin
Partners Research Institute of Molecular Pathology IMP
Dr van Hul,Wim Vienna, Austria
Department of Medical Genetics Dr Sedlmeier, Reinhard
University of Antwerp Ingenium Pharmaceuticals AG
Antwerp, Belgium Martinsried, Germany
Dr Charnay, P Dr Ferrari, Serge
INSERM U368 Geneva University Hospital
Ecole Normale Superieure Geneva, Switzerland
Paris, France Dr Mundlos, Stefan
Prof. de Vernejoul, Marie-Christine Research Group Development & Disease
INSERM U606 Max Planck Institute for Molecular Genetics
Hpital Lariboisir Berlin, Germany
Centre Viggo Petersen Dr Hrab de Angelis, Martin
Paris, France GSF National Research Centre
Dr Levi, Giovanni Munich, Germany
CNRS UMR5166 - MNHN
Evolution des Rgulations Endocriniennes
Paris, France
Dr Lwik, Clemens Acronym: ANABONOS
Department of Endocrinology C4R EC contribution: 3 000 000
Leiden University Medical Centre Instrument: Specific Targeted Research Project
Duration: 36 months
Leiden,The Netherlands Starting date: 01/03/2004

153
HUMAN DEVELOPMENT OSTEOGENE

AND AGEING
Molecular mechanisms of bone homeostasis
Summary Primary OP is a disease of unknown aetiology that is usually divided

into postmenopausal and age-related OP although there are unifying
Osteoporosis (OP) is a metabolic bone disease characterised by loss features.The broad argument is that the dynamic processes of bone
remodelling that comprise bone homeostasis have somehow failed.
of bone mass and disturbed bone microarchitecture compromising
The conventional view is that the balance of production of bone by
bone strength and thereby pre-disposing for fractures. OP is a major means of osteoblasts cannot compensate for bone resorption due to
health problem and of increasing concern in the European the activities of osteoclasts. These overall facts are clear and
parathyroid hormone (PTH) has been recognised as not only a
Community.The disease shows a strong gender bias in which genetic
potential catabolic influence but also therapeutically available as an
predisposition is important and a major predictor of our ability to anabolic influence.
reach and sustain optimal bone mass.The current project is focused
The molecular composition of the bone extracellular matrix in OP
on improving the understanding of the molecular mechanisms is considered largely unaltered,but surprisingly little attention has been
involved in bone homeostasis, and a main emphasis will be on the paid to this aspect.
anabolic aspects. New knowledge is sought using contemporary
array technology and functional genomics building on the recently Aim
definition of the human genome.A major target will be identification The driving force for this project is that the molecular mechanisms
of the mRNAs and proteins that exercise a central role in the causing or leading to OP are not sufficiently known to create
substantial evidence-based knowledge for early diagnosis, prevention
building (anabolic) phases of bone metabolism, including but not
or causal treatment of the disease.Thus a main aim of the project is
limited to those regulated by parathyroid hormone. Selective to combine genomic data (sequence and microarray expression data)
stimulation of anabolic effectors will, it is argued, form the basis for with functional genome research and proteomics directed at
new treatment modalities that will increase new and fully-functional identifying anabolic target genes in the skeleton. In this way the
OSTEOGENE initiative seeks to provide a link between gene function
bone formation. This approach contrasts
with many contemporary regimes of
treatment that primarily inhibit bone
resorption, thus increasing the amount of
more or less worn tissue.A special attempt
will be made to identify genetic markers
that can be used for early identification of
people at risk for later development of
osteoporosis.
Problem
Bone is a dynamic tissue that is continually
remodelling throughout life. In all ageing
people this profit and loss process favours
loss of bone mass. Consequently, many de-
velop osteoporosis with considerably
enhanced susceptibility to fractures with up
to 30% mortality and massive, lasting
morbidity. In fact, OP represents the most
prevalent and incapacitating disease of
women after 50 years of age and the
increased incidence of the disease also
among men has made it a serious threat to
healthy ageing of both genders in Europe.

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HUMAN DEVELOPMENT
AND AGEING
and disease as a frame-work for stimulating biomedical commercial

activities in the areas of early diagnosis, prevention and treatment of
OP. The project will be undertaken by a multidisciplinary team Coordinator
including medical practitioners, molecular and cellular biologists and
Prof. Gautvik, Kaare M
biochemists, all with an inter-national track record.
Department of Clinical Biochemistry,
The long-term aim will be a reduction in the impact of OP in Europe
brought about by application of appropriate evidence-based thera- Division of Laboratory Medicine
peutic and preventive medicine.
Ullevl University Hospital
Kirkeveien 166
Expected results
0407 Oslo, Norway
The results of this project will substantially add to the existing
knowledge base regarding: Phone: + 47 957 42 125
1. association between genetic polymorphism and development of OP Fax: + 47 22118189

in humans; E-mail: kaare.gautvik@basalmed.uio.no
2. possible identification of OP disease genes through genetic and Project web-site: Not yet operative
post-genomic studies in man and animals;
Key words: osteoporosis, gene profiling, bone anabolic
3. improvement of basic insight into osteoblast and osteoclast effectors, genetic polymorphism
regulation and their matrix interactions, and intra-/intercellular
molecular signalling as it relates to bone remodelling;
Partners
4. the chemical nature and significance of bone matrix proteins and
their molecular interaction in the bone remodelling process; Institute of Pathology, University of Oslo, Rikshospitalet
University Hospital, Norway
5. the bone remodelling process and its regulation by key anabolic
effectors including PTH; Endocrine Section, Department of Medicine,
Rikshospitalet University Hospital, Norway
6. genes and gene products that are associated with or causally linked
to bone formation. Department of Cell and Molecular Biology, Section for
Connective Tissue Biology, Biomedical Centre, Lund
University, Sweden
Division of Bone Disease, University Hospital, Geneva,
The project describes how to obtain for the first time an overview Switzerland
of OP-associated and -related genes and gene products defining
a risk profile or genetic susceptibility. This strategy will form the School of Clinical Laboratory Sciences, University of
basis for developing a diagnostic genetic test for the early Newcastle,The Medical School, United Kingdom
detection of OP carried out on the mRNA or protein level. The Department of Experimental Medicine, School of
projected objectives and deliverables represent major Medicine, Bone Biopathology Laboratory, LAquila, Italy
contributions to the medical diagnosis, care and treatment of OP
compared to the present state-of-the-art where OP is under- Immunodiagnostic System, Boldon, United Kingdom
diagnosed and detected late in the disease, frequently not until the
first fracture. An expected outcome after compiling, analyses and
verification of the data, is the capacity to move towards
Acronym: OSTEOGENE
development of a genetic test for the early diagnosis or detection Project number: LSHM-CT-2003-502941
of patients at risk for developing osteoporosis. The novel EC contribution: 2 000 000
knowledge generated in these studies will found the basis of new Instrument: Specific Targeted Research Project
treatment modalities aiming at increasing bone formation rather Duration: 36 months
than reducing bone resorption.

155
HUMAN DEVELOPMENT AGEACTION

AND AGEING
Realising the potential of biological ageing

research
Summary little effective linkage between other areas of activity (social, medical,
economic, engineering) and biological ageing research, which aims
AGEACTION aims to structure a process to: (i) develop a stronger to understand the nature of the ageing process itself what causes
ageing, what can modify it, what underlies the continuing increases
sense of common purpose to deliver the knowledge base that will
in life expectancy and declines in mortality of the oldest-old across
extend health, reduce dependency, and improve quality of life for Europe, and how biological ageing interacts with other factors that
Europes older people; (ii) identify the links between biological ageing influence the lives of older people. This lack of interaction has
resulted in a failure so far to exploit important linkages and to make
research and the underpinning mechanisms of a very wide range of
the most of the enormous opportunities which exist to harness the
medical conditions (disability, frailty, disease) for which age is the single growing understanding of the biological nature of the ageing process
biggest risk factor; (iii) identify links between biological ageing research to help improve the health (understood in the WHO sense of
and social factors such as nutrition,education,lifestyle,housing,transport complete mental, physical, and social well-being) and quality of life
of Europes older people.The reasons for the present situation are
and culture that will help to exploit synergies that can lead to extended easily understood. First, biological ageing research is relatively new
health, reduced dependency, and improved quality of life for older and is itself still fragmented. Second, recent advances in biological
people; (iv) stimulate new interactions between biological ageing ageing research have overturned many of the traditional
conceptions about ageing, but awareness of this has yet to influence
research and technological innovation that can lead to extended health, other spheres of activity.Third, no suitable action has yet taken place
reduced dependency, and improved quality of life for older people; (v) to bring together the various groups that need to engage with the
stimulate closer engagement between biological ageing research and difficult but essential task of building the necessary bridges between
biological ageing research and other domains.
industry across a range of activities leading to creation of new business
opportunities,particularly the formation of SMEs to exploit and develop
Europes growing research capability in biological ageing research; (vi)
Aim
create closer interactions between biological ageing research and those The main aim of the AGEACTION SSA is to structure a process
culminating in a high-level conference that will provide a unique
involved in financial planning in order to take better account of new
opportunity to realise the potential of biological ageing research in
insights into factors that affect life expectancy, health expectancy, and Europe, in the two senses of coming to awareness, and making
projected financial needs (including health and social support) for older something happen or real.Specifically,AGEACTION has the following
people; (vii) provide for Europes older people (and younger people objectives:
the future old) opportunities for greater awareness and more accurate 1.To set in motion a process that will enable biological ageing
researchers to develop a stronger sense of common purpose and
reporting of advances in biological understanding of the ageing process
shared potential to deliver the knowledge base that will extend
that can lead to informed decision-making and empowerment to health, reduce dependency, and improve quality of life for Europes
maximise opportunities for healthy old age; (viii) give Europes policy- older people.
makers a clearer understanding of the nature of the ageing process and 2.To set in motion a process that will identify the links between
of the potential arising from the above activities. biological ageing research and the underpinning mechanisms of a
very wide range of medical conditions (disability, frailty, disease) for
which age is the single biggest risk factor.
Problem 3.To set in motion a process that will identify links between biological
Europe faces the immense challenge of unprecedented increase in ageing research and social factors such as nutrition, education,
life expectancy, which will continue into the 21st century.Although lifestyle, housing, transport and culture that will help to exploit
this state of affairs is the essentially positive outcome from multiple synergies that can lead to extended health, reduced dependency,
improvements in health care and socioeconomic circumstances, it and improved quality of life for older people.
nevertheless presents great strains for all member and associated
4.To stimulate new interactions between biological ageing research
states of the European Union in terms of increasing prevalence of
and technological innovation, including information technology,
age-related health problems and the growing financial implications
nanotechnology and assistive technologies across a wide range that
for pensions, etc. It is widely recognised that in order to meet this
can lead to extended health, reduced dependency, and improved
challenge there needs to be multidisciplinary coordination of
quality of life for older people.
research and development effort. However, to date there has been

156
HUMAN DEVELOPMENT
AND AGEING
5.To stimulate closer engagement between biological ageing research

and industry across a range of activity including pharmaceuticals,
nutraceuticals, diagnostics, nutrition, and lifestyle products leading Coordinator
to creation of new business opportunities and particularly the Prof. Kirkwood,Thomas B L
formation of SMEs to exploit and develop Europes growing research
capability in biological ageing research. University of Newcastle upon Tyne
6. To create closer interactions between biological ageing research Henry Wellcome Laboratory for Biogerontology
and those involved in financial planning (actuaries, insurance Institute for Ageing and Health
companies, pension providers, etc) in order to take better account
of new insights into factors that affect life expectancy, health Newcastle upon Tyne NE4 6BE, United Kingdom
expectancy,and projected financial needs (including health and social Phone: +44 191 256 3319
support) for older people.
Fax: +44 191 256 3445
7.To provide for Europes older people (and younger people the
future old) opportunities for greater awareness and more accurate E-mail:Tom.Kirkwood@ncl.ac.uk
reporting of advances in biological understanding of the ageing Project web-site: To be developed
process that can lead to informed decision-making and
empowerment to maximise opportunities for healthy old age. Key words: ageing, longevity, health, age-related diseases,
quality of life, interdisciplinary research,
8.To provide for Europes policy-makers a clearer understanding of technology, genetics, nutrition.
the nature of the ageing process and of the potential arising from
these activities.
Acronym: AGEACTION
Expected results Project number: LSHM-CT-2005-512053
The main result will be the organisation of a high-level conference Instrument: Specific Support Action
addressing the aims of the project. Duration: 24 months
To achieve this result a number of enabling results will be required,
including:
(i) the establishment of relevant sector panels to define the agenda;
(ii) the identification of venue, dates and participant lists;
(iii) the preparation of background and supporting materials;
(iv) the organisation of appropriate dissemination activities;
(v) and the establishment and operation of procedures to maximise
effective follow-through of the conference outputs.
The project has a wide range of potential applications which are
directly related to its aims.

157
Cancer
INTACT 162
BIOCARE 164
Angiotargeting 166
PRIMA 168
Active p53 170
EMIL 173
TRANSFOG 176
FIRST 179
CANCERDEGRADOME 182
STROMA 185
Mutp53 187
MOL CANCER MED 191
EUROXY 194
MAESTRO 195
CCPRB 196
eTUMOUR 198
TRANSBIG 200
European LeukaemiaNet 202
DNA METHYLATION 206
European MCL Network 209
BRECOSM 212
MetaBre 214
ENACT 217
PROTHETS 219
P-MARK 221
EUSTIR 223
EUROCAN +PLUS 225
CANCER Introduction
1st Call:
FP6-2004-LIFESCIHEALTH
LSH-2002-2.2.0-1 Translating basic LSH-2002-2.2.0-3 Networking for

knowledge of functional oncogenomics treatment and/or prevention clinical
into cancer diagnoses and treatment trials (phase I and II) aimed at improving
clinical practice in the light of new
- INTACT 162
molecular knowledge
- Active p53 170
- TRANSBIG 200
- TRANSFOG 176
- European LeukaemiaNet 202
LSH-2002-2.2.0-2 Multidisciplinary
LSH-2002-2.2.0-4 Innovative research in
research to explore and validate
radiation therapy
molecular targets for innovative
treatment - FIRST 179
- Angiotargeting 166 - MAESTRO 195
- PRIMA 168
- CANCERDEGRADOME 182 LSH-2002-2.2.0-5 Molecular imaging for
early detection of tumours and
- STROMA 185
monitoring of treatment
- Mutp53 187
- EMIL 173
- MOL CANCER MED 191
- eTUMOUR 198
- EUROXY 194
- BIOCARE 164

160
CANCER
3rd Call:
FP6-2004-LIFESCIHEALTH-4
LSH-2002-2.2.0-6 Networking of quality LSH-2004-2.2.0-9: Feasibility Study for

controlled cancer registries and the coordination of national Cancer
repositories for molecular epidemiology research activities.
and quality assessment
- EUSTIR 223
- CCPRB 196
- EUROCAN +PLUS 225
LSH-2002-2.2.0-7 Molecular mechanisms

involved in organ-specific metastatic
growth processes in breast cancer
- BRECOSM 212
- MetaBre 214
LSH-2002-2.2.0-8 Translational research

on promising predictive and prognostic
markers
- DNA METHYLATION 206
- European MCL Network 209
- ENACT 217
- PROTHETS 219
- P-MARK 221
LSH-2002-2.2.0-9 Molecular mechanisms

of cancer-related pain
LSH-2002-2.2.0-10 Workshop on
correlative laboratory studies relevant to
therapeutic clinical studies

161
CANCER INTACT
Identification of novel targets for cancer therapy
Summary
Despite intensive worldwide research efforts, cancer remains a
devastating, often poorly treatable disease.We propose to develop and
apply new functional genomics technologies that will provide unique
approaches to the design of new pathway-specific cancer therapies.Our
specific objectives are:
1. to develop large-scale functional genomic analysis to identify novel

mechanisms involved in cancer development; specifically, we will
generate the tools and technologies to carry out genome-wide loss-
A. Schematic drawing of the pSUPER vector and the predicted stem-loop
of-function screens in mammalian cells. precursor transcript that is processed by intracellular RNases to siRNA-
like molecules. B. Schematic drawing of a gene-specific pSUPER insert,
2. to apply these technologies to specific models of major human cancer-
consisting of two 59-mer oligonucleotides that contain a 19 nt gene-spe-
causing pathways to define novel targets for therapy. cific insert, a loop sequence, followed by the reverse-complement of the
same 19 nt gene-specific insert and a termination signal (5xT).
3. to use existing and generate novel mouse models and non-invasive
tumour imaging to validate and assay cancer gene function in vivo and
2.To generate novel tools in the form of RNAi retroviral libraries
to develop new treatment modalities.
(mouse and human), cell-based assays, mouse models and reagents
4. to develop cell-based assays for cancer-relevant genes and pathways that will be distributed on a non-profit cost-charge to academic
researchers in the European Community.
that will serve as readout for the identification of anticancer agents
3.To develop novel technologies for target validation in mouse and
through the screening of chemical compound libraries.
to develop mouse models to validate the role of the identified genes
5. to distribute and disseminate the novel technologies for the study of in the development of cancer.
gene function in vitro and in vivo within the consortium and to 4.To develop cell-based assays for cancer-relevant genes that will
researchers in the European Community. serve as a starting point for the identification of anticancer agents
through the screening of chemical compound libraries.At the end
To reach these objectives we have formed a multidisciplinary of the four-year programme, collaboration with large
pharmaceutical companies will lead to further refinement of lead-
research consortium, including top scientists with extensive
compounds and the possible introduction of novel anti-cancer
experience in developing innovative genomics technologies and agents into clinical trials.
with an excellent track record in identifying key signaling molecules
5.To develop novel technologies to study gene function in vitro and
involved in cancer, as well as SMEs with experience in identifying vivo, and to distribute these technologies within the consortium
cancer-relevant genes and in screening chemical compound and subsequently to researchers in the European Community.
libraries.The location of most of the partners at leading European
cancer centres will ensure optimal conditions for the development Specific phases of the project
of novel cancer-specific treatments. 1. Establishment of the technology platforms:
a. development of bar-code screen for the human siRNA library
Scientific and technological b. generation of mouse siRNA library
objectives c. development of protocols for high-efficient reverse infection of primary
1. Use large-scale functional genomics,in particular genome-wide loss- cells
of-function screens, to identify novel mechanisms, including novel
d. development of ERM-tag screen
oncogenes and tumour suppressor genes, involved in the
development of human cancer. e. development of lentivirus vectors and protocols for making transgenic
mice.

162
CANCER
Coordinator
Prof. Helin, Kristian
Biotech Research & Innovation Centre (BRIC)
Fruebjergvej 3
2100 Copenhagen, Denmark
Phone: + 45 39 17 96 66
Fax: + 45 39 17 96 69
E-mail: kristian.helin@bric.dk
Project web-site: http://www.imt.uni-marburg.de/intact/
Key words: RNAI Libraries, Oncogenes,Tumour suppres-
sors, Signaling, Mouse models, Compound medical libraries.
Partners
Stable siRNA expression vector contains a gene specific identifier. Prof. Pelicci, Pier Giuseppe,
Expression vectors for siRNAs encode a short hairpin RNA molecule European Institute of Oncology,
(RNA hairpin) (Brummelkamp et al., 2002b). Milan, Italy
Berns, Anton ,
Cancer Institute,
2. Establishment of cellular models for performing ERM-tag and siRNA Amsterdam,The Netherlands
library screens. Bernards, Ren,
Cancer Institute,
3. Determination of cancer relevance of identified genes through Amsterdam,The Netherlands
assessment of their expression level in primary human tumors, Van Lohuizen, Maarten,
characterisation of their biological function, and generation of Cancer Institute,
mouse models. Amsterdam,The Netherlands
Blasco, Maria,
4. Development of cell-based assays for newly identified cancer
Spanish National Cancer Center,
relevant genes for the use of screening of compound libraries.
Madrid, Spain
Serrano, Manuel,
Spanish National Cancer Center,
Madrid, Spain
Baccarini, Manuela,
Vienna Biocenter,
Vienna, Austria
Schmitt, Clemens,
Max-Delbrck-Center,
Berlin, Germany
Eilers, Martin,
University of Marburg,
Marburg, Germany
Trumpp, Andreas,
ISREC,
Auguet, Michel,
ISREC, Lausanne
Karen Vousden,
Beatson, CR-UK, Glasgow, United Kingdom
Dejean, Anne,
Pasteur,
Paris, France
Bar code screen. Schematic outline of bar code siRNA hybridisa- Morphochem,
tion screen to identify genes that increase cellular fitness after Munich, Germany
stress or decrease cellular fitness after stress.
Agendia,
Acronym: INTACT
Project number: LSHC-CT-2003-506803
Duration: 48 months

163
CANCER BIOCARE
Molecular imaging for biologically optimised

cancer therapy
Summary Project objective
Early tumour detection and response monitoring require maximum BioCare is focused on developing new techniques and approaches to
increase the sensitivity and specificity of existing tumour imaging
sensitivity and specificity of the imaging method. During the 1970s
techniques as well as introducing more systematic and adaptive
and early 1980s, Computed Tomography (CT) with diagnostic X-rays approaches based on high-quality tumour imaging. The objective of
made a revolution in accurate delineation of normal tissue anatomy the project is to:
as well as gross tumour growth. In the mid 1980s and 1990s, magnetic improve and speed up the implementation of PET-CT imaging in
resonance imaging and spectroscopy allowed even more accurate cancer management
differential diagnostics of soft tissue malignancies with the possibility develop new European intellectual property to improve tumour
of distinguishing between tumour tissues,oedema and normal tissues. imaging by more specific tumour tracers. They will result in
The integration of positron emission and X-Ray computed considerably increased resolution, sensitivity and specificity in
tumour detection.
tomography in one unit is bringing another diagnostic revolution to
tumour imaging. By combining these two imaging modalities, an BioCare is subdivided into four major activities addressed through
nine work packages.The areas are namely: PET camera development,
unprecedented accuracy in the delineation of the tumour on a development of new tracers, experimental and clinical validation and
background of normal tissue anatomy is achieved. implementation of the techniques above in medical oncology.
Although significant progress in cancer cure rates have been achieved Work package 1
in the past,approximately 45% of patients still succumb to their disease Design of detectors for whole body PET systems with a high intrinsic
due to local (~25%) and/or distant (2025%) tumour recurrence. Early resolution. Investigation of the possibility of integrating a PET-CT
device with a radiation therapy unit with an ergonomic design both
detection of small tumour deposits may allow successful treatment.
for patients and personnel to simulate imaging of the tumour response
Moreover, lack of individualised tumour characteristics leads to and responsiveness as well as dose delivery in vivo.
erroneous over - and under-treatment and precludes individualised
Work package 2
therapy selection. Molecular tumour imaging is an active area of
Methods for real-time monitoring of the apoptotic response to radio
development and may provide a non-invasive tool to tackle some of
therapy and to predict early responses during the course of therapy
these problems as it has benefited substantially from the recent for optimising therapy planning and making prognostic evaluations.
development of our knowledge about molecular genomics and
Work package 3
proteomics pathways. The development is very rapid and many new
To promote understanding of the complex processes induced by
approaches are likely to be developed in the coming years. cancer therapy, especially radiation therapy, through a comprehensive
The most commonly used radiotracer used; fluorodeoxyglucose evaluation of established (e.g. FDG, FLT) and new tracers for therapy
response assessment in human tumour models.
(FDG), is not tumour-specific, as all regions with an increased
metabolic rate will show an elevated glucose uptake. More specific Work package 4
tumour markers allowing an even more accurate imaging of the Development of radiolabelled aptamers, small tailor-made
oligonucleotides aimed at tumour-specific target structures for
tumour clonogen density are therefore of importance as they may
individually optimised cancer treatment.
image e.g. perfusion, hypoxia, amino acid and receptor status.
Work package 5
Methionine and other amino acids are already available as tracers
and, although they may be better than FDG, they may still not be Development of molecular imaging methods that can vissualize and
quantify temporal and spatial changes in hypoxia in human tumours.
sufficiently specific, since they are incorporated in all tissues that
are being renewed. For some tumours, there are more specific Work package 6
markers such as 11C-Choline, and FHBC or FDHT (Fluorodihydro- To investigate the use of state-of-the-art Positron Emission
testosterone) for imaging androgen receptors in prostate cancer. Tomography with Molecular Imaging and X-Ray CT-based anatomical
imaging to monitor the radio- and chemotherapy of cancer and to
Vasculature could be visualised by known tracers such as ammonia
trace the early response of the tumour of interest by quantifying the
( 11CH or water (H215O).
3) sensitivity of the tumour in three dimensions in vivo.

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CANCER
Work packages 7 & 9

PET-CT-SIM molecular tumour imaging and treatment simulation with Coordinator
conformal RT to make the concept of a biological target volume
Prof. Brahme,Anders
reality leading to biologically optimised molecular tumour imaging and
radiation treatment planning. Department of Medical Radiation Physics
Work package 8 Karolinska Institutet
To examine molecular targets involved in tumour angiogenesis using 171 77 Stockholm, Sweden
anti--angiogenetic probes and to investigate the value of function-
Phone: + 46 8 517 724 96
related indices of response (e.g. blood volume, flow, permeability,
metabolism, etc.) to non--invasively monitor the effects of therapy. E-mail: anders.brahme@radfys.ki.se
Key words: Tumour imaging, PET, PET-CT, MRSI, Optic
tumour imaging,Tumour response monitoring.
Partners
Dresden University of Technology, Germany
The Victoria University of Manchester; United Kingdom
Forschungszentrum Rossendorf e.V., Germany
University of Maastricht, The Netherlands
Katholieke Stichting UMC St. Radboud,The Netherlands
Aarhus University Hospital, Denmark
Institut Gustave-Roussy, France
Universitt Hamburg, Germany
Universit Catholique de Louvain, Belgium
Universitair Ziekenhuis Gasthuisberg, Belgium
The Netherlands Cancer Institute,The Netherlands
Soltan Institute for Nuclear Studies, Poland
University of Turku, Finland
PencilBeam Technologies AB, Sweden
PEVIVA AB, Sweden
RayClinic AB, Sweden
European Society for Therapeutic Radiology
and Oncology, Belgium
European Organization for Nuclear Research,
Switzerland
RayTherapy Imaging AB, Sweden
RaySearch MedicalAB, Sweden
Acronym: BIOCARE
Duration: 54 months

165
CANCER Angiotargeting
Multidisciplinary research to explore and validate

molecular targets for innovative treatments
Summary Angiotargeting combines front-line knowledge of basic and clinical
research involving global gene and protein analyses, stem cell research,
Solid tumour growth depends on a continuous supply of nutrients by physiological mechanisms, advanced animal model systems, molecular
new blood vessels that grow into the tumour. This process, termed imaging and clinical research. The consortium exploits the research
tumour angiogenesis, is regulated by a number of complex factors expertise accumulated at six European universities,six European research
involving both tumour and host cells. How the tumours communicate institutions and two biotechnology companies with a common goal of
with the normal cells to produce blood vessels has during the last years finding new therapeutic targets,that cannot be achieved at national level.
gained increasing attention and it has recently been shown that targeting
the host vasculature has a therapeutic potential for certain tumours. Scientific objectives
The Integrated Project Angiotargeting focuses on the identification of 1.To co-ordinate multidisciplinary research and basic knowledge
novel genes and gene products that regulate tumour angiogenesis and within the field of tumour cell matrix interactions, to provide the
on validating such products as therapeutic targets. In addition, novel basis for novel therapeutic strategies against tumour progression.
therapeutic strategies will be evaluated in preclinical models as well as 2.To get a comprehensive understanding of how tumours generate
vascular supply by using advanced genetic model systems.
in the clinic.Angiotargeting will therefore open new avenues in the search
for new therapeutic compounds towards malignant disease. 3.To forward new technological approaches, including high
throughput screening technologies within the field of tumour cell-
Angiotargeting focus on the identification and validation of novel matrix interactions,to define and validate key molecular targets that
control tumour angiogenesis.
therapeutic targets on tumour blood vessels. Such targets will be used
in the development of novel therapeutic strategies towards tumour blood 4.To assess and validate strategies that disrupt and abrogate tumour
angiogenesis and invasion.This includes the validation of novel as
vessels growth.
well as described potential therapeutic targets towards the tumour
The concept of treating genetically stable vascular cells, rather than vascular and invasive transcriptome and proteome.
drifting tumour cells, has gained increasing acceptance in the scientific 5.To establish comprehensive bioinformatics tools for the analysis of
high throughput gene and protein data,from defined cell populations
community. It is essential that European research centres co-ordinate
within tumours, with the aim of validating targets by assessing
their research efforts within this promising area of science and that therapeutic efficacy in preclinical as well as clinical models.
innovations within the field of angiogenesis are supported at European
6.To implement state of the art platforms for preclinical and clinical
level.The Angiotargeting consortium is contributing particularly to the assessment of newly developed compounds.
knowledge base for the development of the European biotechnology
industry within the field of angiogenesis.
Angiotargeting represents an added value on a range of aspects related

to integration of research in Europe by combining some of the most
qualified research groups and establishing a European-based strategy for
treatment of cancer targeting the tumour vascular supply.

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CANCER
Coordinator
Prof. Bjerkvig, Rolf
University of Bergen
Musplass 1
5020 Bergen, Norway
Phone: + 47 55 58 63 52
Fax: +47 55 58 63 60
E-mail: rolf.bjerkvig@pki.uib.no
Key words: Tumour Targetting, Angiogenesis
Partners
University of Bergen, Norway
European Institute of Oncology, Milan, Italy
University of Uppsala, Sweden
Netherlands Cancer Institute,The Netherlands
Xantos Biomedicine AG, Germany
Maastricht University,The Netherlands
University of Oxford, United Kingdom
Vrije Universiteit Medical Centre, Amsterdam,
The Netherlands
University of Oulu, Finland
Institute of Experimental Medicine, Academy of Sciences
of the Czech Republic
Centre Recherche de Public Sant, Luxembourg
The Karolinska Institute, Sweden
Acronym: Angiotargeting
Duration: 48 months

167
CANCER PRIMA
Summary therapy-unresponsive bone metastatic disease will use functional

genomics and expression profiling as technology platforms.These
Prostate cancer is one of the most common malignancies in the technology platforms will also be used to identify novel candidate
targets for treatment. A specific bioinformatics platform will be
western male population. In Europe, approximately 40 000 men die
developed to analyse all collected data. In the targeted discovery
of prostate cancer each year and that number is likely to increase, phase, a great number of candidate target genes will be identified
due to the ageing population,to roughly 60 000 men in 2020.Therefore that, in addition to already available targets from earlier co-
llaborative programmes, need to be phenotypically and/or
prostate cancer is a significant medical problem with which the
functionally validated. Phenotypical validation will be performed in
European Community will be confronted increasingly in the oncoming archival material of patients with a well documented follow-up, in
decades. For localised prostate cancer, radical therapies aiming at all stages of the disease process. In addition, high-throughput
eradicating all malignant processes in the prostate gland are available functional, cell-based analysis and molecular target validation will
be performed by knocking down genes that are over-expressed in
that can cure the patient.However,if the malignant process has locally hormone refractory or metastatic prostate cancers using RNA
or distantly spread, no curative medical intervention is currently interference.The knowledge obtained from the targeted discovery
available. Since the early 1940s androgen ablation therapy has been phase and validation phase will be used to establish assays which
will in turn be used for high throughput screening of low molecular
the mainstay in an attempt to control prostate neoplasms, but weight compounds (i.e., more than 25 000 compounds).The assays
unfortunately this is only of a palliative nature and tumour progression will use easy-to-upscale formats and reporters that can be easily
due to the expansive growth of cancer cells that are unresponsive to read out.
currently available hormone therapies is inevitable. Furthermore, The final phase of the project will be the testing of interesting
prostate cancer cells have a strong tendency to spread to the bone, compounds for their ability to efficiently interfere with cancer cell
proliferation and/or survival in a bone environment in the absence
a site where metastases cause great morbidity, ultimately leading to of androgens.The lead compounds will be tested for their efficacy
a painful death. in models for bone metastatic prostate cancer. Hence translation
of the obtained knowledge into therapeutic strategies is an
integrated part of the project.
Research plan
In the PRIMA project a multidisciplinary effort is proposed to
explore the pathways that lead to the most lethal aspect of prostate
Consortium
cancer, i.e., hormone-therapy-unresponsive bone metastatic The PRIMA consortium is organised in a kind of matrix structure,
lesions. It has become clear that in the majority of advanced in which the top European research laboratories in the field of
prostate cancers the androgen receptor signalling pathway is active urological oncological research, particularly prostate cancer, have
even in the absence of androgens. European research teams with joined forces with strong disciplinary teams in the field of molecular
a leading role in androgen receptor research will integrate their life sciences. The experimental urology laboratories have the
efforts to exploit androgen receptor mediated signaling as a advantage of covering the distance from the clinical need to the
therapeutic target. This should be achieved by: 1) targeting the experimental research approach and vice versa. Research plans are
androgen receptor itself; 2) interfering with androgen receptor aimed at clinical questions, in the case of this project the treatment
activation by non-steroids; 3) studying non-transcriptional functions of hormone unresponsive prostate cancer.The clinical applicability-
of the androgen receptor; 4) targeting essential androgen receptor driven research efforts of these typical experimental urology
co-factors over-expressed in prostate cancer; and 5) inhibiting those research teams does not allow in-depth investment in platform
androgen receptor target genes which regulate prostate cancer cell technologies, such as genomics, transcriptomics and bio-informatics.
growth, survival and differentiation.The androgen receptor teams Therefore, the efforts are integrated with expert European teams
will join forces with European investigators that study the in molecular endocrinology, bioinformatics, functional genomics,
interaction between prostate cancer cells and the bone micro- expression profiling and design and establishment of (screening)
environment. Expression profiling of members of the TGF- super models. This has resulted in an integrated consortium aimed at
family and signal transduction molecules in cell lines, animal models solving a major clinical issue, i.e., an effective treatment for prostate
and clinical specimens should provide more insight in the role of cancer.
these molecules in the development of bone metastatic lesions.
Furthermore, epithelium-mesenchymal transition will be extensively
studied. The exploration of the pathways leading to hormone-

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CANCER
Related projects
Currently, two other FP6-projects dealing with prostate cancer are
Coordinator
in contract negotiation phase for funding by the EC.The project P- Prof. Schalken, J A
MARK, a STREP, concentrates on the identification and development University Medical Centre St. Radboud
of new prognostic markers for prostate cancer, and GIANT, an IP,
aims at the development of viral and non-viral vectors for the Dept. of Experimental Urology
targeted treatment of prostate cancer. The three consortia are PO Box 9101
closely related and have many existing collaborations. In order to
6500 HB Nijmegen,The Netherlands
adequately inform scientists and urologists about the knowledge
generated by the projects and to get as many clinicians as possible Phone: + 31 24 361 4146
involved in the projects, a team of six urologists and scientists is Fax: + 31 24 354 1222
responsible for external communication and representation of the
E-mail: primaproject@uro.umcn.nl
three consortia.This team includes the three coordinators as well
as people involved in at least two of the projects. Integrated efforts Project web-site: www.primaproject.org
will be made to inform, educate and discuss the progress of the Key words: Prostate Cancer, Androgen Receptor, Bone
projects with the European Urology community through the Metastasis
European Association of Urology (EAU).
Partners
Erasmus Medical Center Rotterdam,The Netherlands
Centre Eurpen de Recherche en Biologie et Mdecine,
France
University of Sheffield, United Kingdom
Turun Yliopisto, Finland
Speciality Chemical Services Holding B.V.,The Netherlands
Medizin Universitaet Innsbruck,Austria
University of New Castle upon Tyne, United Kingdom
Forschungszentrum Karlsruhe GMBH, Germany
Universitaet Bern, Switzerland
University of York, United Kingdom
Centre de Recherche pour les pathologies prostatiques,
France
Leiden University Medical Centre,The Netherlands
University of Tampere, Finand
Weizmann Institute of Science, Israel
The Chancellor , Master and Scholars of the University
of Cambridge, United Kingdom
Acronym: PRIMA
Duration: 60 months

169
CANCER Active p53
Manipulating tumour suppression:

a key to improve cancer treatment
Summary
The prevention of human cancer development
depends on the integrity of a complex network of
defence mechanisms that help cells to respond to
various stress conditions. A key player in this
Outline of
network is the p53 tumour suppressor protein. By
the consortium
inducing efficient growth inhibition, p53 eliminates
cancer cells thereby preventing the development of
human malignancies.These functions of p53 often
determine the efficacy of anti-cancer therapies.
Although p53 is frequently mutated in some
cancers, in about 50% of all human cancers p53 is
non-mutated and could,in principle,be activated to
prevent tumour progression.This situation is prevalent among a wide Problem
range of cancers, notably breast carcinoma. However, p53 activity is
Cancer is the second leading cause of death in European countries,
hampered by malfunction of its many modulators, such as Mdm2 or and one of the most imminent health problems in the developed world.
p73, which govern p53 tumour suppressive activity by acting upstream The p53 protein is generally recognized as the key determinant of
and/or downstream of p53. There is therefore a crucial need to tumour suppression. It has been declared by the European Union that
a large co-operative effort is needed to ensure that every European
understand how p53 modulators contribute to human malignancies. citizen will rapidly profit from the revolution of knowledge in cancer
Based on this information, we propose to develop rational therapeutic management (Philippe Busquin). The presence of wild type p53 is
approaches to manipulate p53 modulators, thereby wakening the particularly prevalent in breast cancer, the type of cancer that stands
at the centre of the European cancer policy.Since breast cancer affects
sleeping tumour suppression activities of p53, allowing it to eliminate
mostly (though not exclusively) women, breast cancer research is also
cancer cells.A carefully structured consortium comprises 19 academic an important task to implement the gender dimension into basic
research centres and SMEs (see diagram). It will interactively build a research. For these reasons, we will choose breast cancer as one of
our focuses in this block of work.Moreover,a non-mutated but inactive
technology platform to comparatively identify,characterise and evaluate
p53 is also found in a high percentage of the most frequent intracranial
the regulatory roles of p53 modulators and define the mechanisms of tumour of children, neuroblastoma. Since paediatric tumours are
their action. Large-scale gene functional analyses will be conducted to particularly dramatic events for patients and their families, it appears
identify relevant signalling pathways that impair or mediate tumour appropriate to put another focus on this tumour species.
suppression by p53. These analyses will include p53 activators and

inhibitors,p53 homologues p73/p63,and dissection of p53 target genes Aim
mediating apoptosis and growth arrest. Our links with highly profiled The principal aim of this proposal is to ease both diagnosis and prognostic
clinical partners and our access to large,well-characterised and clinically classification, as well as the efforts towards novel therapy regimens to
treat patients suffering from breast cancer and neuroblastoma. Overall,
documented sample collections will enable the evaluation of diagnostic the integrated action of our consortium is aiming at re-establishing
expression profiles, and their potential prognosis value in cancer. tumour suppressor activity in cancer, thereby translating basic knowledge
Particular emphasis will be directed towards translating the of functional oncogenomics into cancer diagnoses and treatment, and
contributing to leadership in European health technology.
information on p53 regulation into the development of new anti-cancer
therapies. p53 regulatory proteins will be used for the identification of
new molecular targets for drug discovery.

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CANCER
Expected results
The overall goals of this integrated effort are to understand:
1. which modulators determine the tumour-suppressive activities of
the p53 family members
2. by what mechanisms these modulators affect the tumour
suppression activities
3. how the expression and activity of p53 modulators is regulated
4. whether p53 modulators affect the biological characteristics of
tumour cells
5. whether the status of p53 modulators correlates with the clinical
outcome and can be used to determine the individual prognosis
6. whether and how p53 modulators can be targeted by therapeutic The four blocks are linked as outlined.These links are formed
strategies, and be manipulated towards regaining tumour according to the biological activities governing p53, and therefore,
suppression. the scheme simultaneously depicts biological dependencies as well
7. disseminate the knowledge that will be produced to practically all as the mode of collaboration within the consortium. Activators of
the interested parties including medical doctors,and managerial staff p53 frequently act by antagonizing p53 inhibitors, and vice versa,
in the industries this will be taken into account by networking accordingly between
the blocks 1 and 2. Activators and inhibitors of p53 may act on
8. familiarise SMEs with scientific research work and state-of-the-art
technology that will provide the necessary know-how for the p73 and p63 as well, and this was shown to be true in a number
improvement of their services and competitiveness. of cases.Therefore, each regulator of p53 will be assessed regard-
ing its impact on p53-homologues as well, by collaborative efforts
between Block of work 3 with blocks 1 and 2. Finally, the assess-
ment of p53 downstream activities, and the development of cut-
ting-edge technologies to analyze them, will be used throughout the
consortium.Therefore, Block of work 4 forms a basis not only to
reach excellence on its own, but also to effectively advance the
progress of blocks 1, 2 and 3
The ultimate general objective of this research proposal is to provide
a basis for the re-activation of tumour suppression and the design of
novel therapeutic approaches to combat cancer. In particular, we are
aiming at modulating p53 family activities to decrease resistance of
tumour cells to anti-cancer treatments.Thus, the ultimate goal of this
research proposal is the identification of novel drug targets and
strategies for induction of p53-mediated apoptosis in therapy-resistant
The members of our consortium have identified a number of p53-mod- cancer cells. The participation of the SMEs is expected to play a key
ulators (stage 1), and in some cases, have begun to understand their role to the practical application of the knowledge that will be produced.
mechanisms of action.We are now pursuing an integrated strategy to
advance our knowledge on the nature of these modulators through
stages 2-5, and ultimately to evaluate their potential as candidate drug
targets (stage 6).We are starting from the scenario outlined below.

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CANCER
Coordinator
Dr Blandino, Giovanni Dr Bartk, Jiry
Department of Experimental Oncology Danish Cancer Society
Regina Elena Cancer Institute Dept. of Cell Cycle and Cancer
Via delle Messi DOro 156 Institute of Cancer Biology
Rome, Italy Danish Cancer Society
Phone: + 39 06 52662522 Copenhagen, Denmark
Fax: + 39 06 52662505 Dr Levrero, Massimo
E-mail: blandino@ifo.it Fondazione Andrea Cesalpino
Project web-site: Laboratory of Gene Expression
http://www.europeire.it/Activep53/intro.html Rome, Italy
Key words: tumour suppression, p53, p73, p63, Dr Jochemsen, Aart Gerrit
inhibitors, activators, technology Dept. Molecular and Cell Biology,Tumour Suppressor
Group
Leiden University Medical Center
Partners Leiden,The Netherlands
Dr Dobbelstein, Matthias Dr Selivanova, Galina
Centre of Medical Biotechnology Karolinska Institute
University of Southern Denmark Department of Laboratory Medicine, Stokholm, Sweden
Odense Denmark Dr Del Sal, Giannino
Dr Haupt,Ygal Universit Degli Studi Di Trieste
The Lautenberg Center for General and Tumour Dipartimento di Biochimica
Immunology
Biofisica E Chimica Delle Macromolecole
The Hebrew University - Hadassah Medical School,
Trieste, Italy
Jeruslem, Israel
Dr Iggo, Richard
Dr Kroemer, Guido
Swiss Institute for Experimental Cancer Research
Centre National de la Recherche Scientifique
Oncogene Group
Laboratoire de Gntique Oncologique UMR8125
Dr Deppert,Wolfgang
Institut Gustave Roussy
Heinrich-Pette-Institut fr Experimentelle Virologie und
Villejuif, France Immunolgie an der Universitt Hamburg
Dr Lu, Xin Department of Tumour Virology
Ludwig Institut Fur Krebforschung Hamburg, Germany
Tumour Suppressor Group Dr Lane, David
Ludwig Institute For Cancer Research University of Dundee
London, United Kingdom Department of Surgery and Molecular Oncology
Dr Voudsen, Karen Nethergate, Dundee, United Kingdom
The Beatson Institute For Cancer Research Biotecgen s.r.l.
Tumour Suppressor Laboratory, Department of Biological Sciences
Glasgow, United Kingdom
Institute of Physiology
Dr Rotter,Varda
Lecce, Italy
Weizmann Institute of Science
Dr Moarefi, Ismail
Molecular Cell Biology / Biology
SiREEN AG
Rehovot, Israel
Martinsried, Germany
Dr La Thangue, Nicholas B
University of Glasgow
Biochemistry and Molecular Biology
Institute of Biomedical and Life Sciences, Cathcart Lab
Glasgow, United Kingdom Acronym: Active p53
Dr Melino, Gerry EC contribution: 6 000 000
Medical Research Council Instrument: Integrated Project
Duration: 60 months
Leicester, United Kingdom Starting date: 01/12/2004

172
EMIL CANCER
Molecular imaging of cancer
Summary sample during analysis and are not applicable to whole body and
longitudinal explorations. Hence they fail to recognise the essential
The general objective of the EMIL Network of Excellence is to merge character of cancer, development across time and space.
the leading European research teams in molecular imaging, in On the other hand, in vivo imaging is a repeatable and non-invasive
universities, research centres and small and medium enterprises, to localisation technology with the potential to become the preferred
means for cancer diagnostics and follow-up. However, imaging is
focus on early diagnosis, prognosis and therapeutic evaluation of based on evidencing a contrast between cancer and normal tissue,
cancer. and this is quite challenging to perform in vivo in view of the fact
that cancer cells are a clone of normal cells. Even though anatomic
The EMIL network brings together 58 partners representing 43 bodies imaging can occur in vivo at sub-millimetre resolution, imaging
in 13 European countries, and integrates six technological facilities: techniques based on gross physical differences such as density or
Orsay (France), Turin (Italy), Cologne (Germany), Leiden water content perform poorly in producing a contrast which must
be based on specific imaging agents targeting tumour cells.
(Netherlands), Milan (Italy) and Antwerp (Belgium) around a
Molecular imaging is a new science bridging together molecular
common activity programme including:
biology and in vivo imaging with the aim to detect the expression of
integration activities: creation of a network of technological and specific genes. Imaging science has made sufficient progress in the
last decade to bridge the gap between physiology and molecular
training facilities favouring the mobility of researchers and the biology, and is now at the stage where it can perform molecular
integration of small and medium sized enterprises into the EMIL imaging of gene expression in vivo. Significant advances have occurred
network in molecular imaging modalities, including the nuclear medicine
techniques of SPECT and PET, MRI and spectroscopy which have
dissemination of expertise activities: training, communication, attained resolution sufficient for small animal imaging, and optical
common knowledge management and intellectual property rights imaging, which can now reach unprecedented sensitivities.
research activities:a common research programme with a horizontal

Aim
dimension, making use of methodological tools of physics, biology
The potential of molecular imaging is considerable.
and chemistry necessary for the further development of molecular
imaging (instrument techniques, molecular probes, biological In fundamental research, it allows the visualisation of cell function
and molecular processes in living organisms, in particular the
engineering), and a vertical integrative dimension, bringing together
monitoring of the stages of growth and ageing, the response to
cancer imaging applications (early diagnostic imaging, development environmental factors, the exploration of cell movements, etc.
of new therapies, imaging for drug development). In experimental medicine it identifies the molecular determinants
of pathological processes in situ, evaluates new molecular therapies
Problem such as gene therapy, and accelerates drug development (delivery
of active compounds, efficacy of vectors, etc.).
Cancer is characterised by an uncontrolled proliferation of cells that
With the evolution of imaging techniques and the capacity to transfer
escape the rules of the organism they originate from. For normal
animal data directly into clinical applications, molecular imaging is a
cells, these rules are both spatial (a cells location is defined by its
most promising technique to tackle cancer detection, following the
integration in an organised tissue) and temporal (a cell obeys the
rule of the three Ps: Precocious, Precise and Predictive.
laws of controlled division and death corresponding to its
programmed life cycle). Cancer cells disobey the laws of time and - Precocious: several successive mutations are necessary to make
space, proliferate and invade. a cell cancerous. By detecting genetic anomalies at the very first
mutation, molecular imaging could permit early diagnosis and
The last two decades have witnessed enormous advances in our
prompt intervention right at the start of the cancer-forming
understanding of cancer at molecular level and have demonstrated
process.
that it results from abnormal gene expression in cell clones. Gene
expression analysis techniques are now witnessing systematic - Precise: molecular imaging makes it possible to detect precisely,
compilation of molecular data that can be used to provide accurate in space and time, the gene or genes that are dis-regulated in the
diagnosis and prognosis.These techniques are well-established and cancer cell. The tumour can then be characterised with all the
widely applied to in vitro biological samples, but they destroy the required molecular precision.

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CANCER
- Predictive: the fineness of the information obtained by molecular imaging, (ii) directly study alteration of gene expression, tumour
imaging makes it possible not only to determine the tumour type, cell proliferation and migration in vivo over an extended period
but also to predict its evolution, adapt the treatment and monitor of time in the same animal
its efficacy.
7. to identify in vivo molecular targets of cancer and metastasis
This is essential to: enabling an early diagnosis, assessment of disease progression and
response to therapy
validate in the context of living organisms the targets and drugs
designed by genome data mining and in vitro gene expression 8. to establish imaging-guided patient-tailored therapies
analysis through methods that are both non-invasive and repeatable
9. to develop imaging technologies for in vivo drug screening using
acquire fundamental knowledge about the patterns of gene animal models predictive for human disease and applications to
expression in normal tissues and define the changes in specific gene human clinical trials
expression in cancer
10. to do molecular imaging of apoptosis in cancer.
design and develop drugs targeting cancer-related gene expression
allow precise evaluation of new treatments and new anticancer drugs Potential applications
that are required for progress in cancer management, through
reliable measures of the cancer burden. 1.Tumour diagnosis
2. Follow up of tumour progression
Expected results 3.Therapeutic evaluation
The present initiative is taken to capitalise on the extraordinary
opportunity for studying non-invasively gene expression and
function in cancer, due to recent advances in molecular imaging Coordinator
modalities. Because molecular imaging is fundamentally multi- Tavitian, Bertrand
disciplinary by nature, the instrument for this goal is a Network of
Excellence bringing together genome-oriented scientists with the CEA - SHFJ
various actors of imaging science and the clinicians dedicated to Unit dimagerie in vivo de lexpression des gnes
formulating novel diagnostic methods based on imaging.The general
objectives of EMIL are to: 4 place du Gnral Leclerc
1. coordinate the current effort in EMIL by merging 43 groups from 91401 Orsay, France
universities, research centres and SMEs coming from different E-mail:Tavitian@shfj.cea.fr
scientific and technical fields into one virtual excellence centre
with dedicated technological training platforms and integrated Project web-site: www.emilnet.org
dissemination and management activities Key words: EMIL, molecular imaging, cancer, drug devel-
2. advance EMIL to the scientific, technical and economical status opment, guided therapies, tumour diagnosis,
that should be expected from its value for European citizens, in in vivo imaging of gene expression
order to improve cancer diagnosis follow-up, to promote and
assist in the development of new targeted therapies, and translate
science and technology progress into economical benefits
Partners
Dipartimento di Chimica I.F.M., Universit degli di Studi di
3. act as leverage for a strong technological development that can
Torino,Turin, Italy
be fuelled through specific research and development projects.
Dept. of Neurology, Lab for Gene Therapy and Molecular
And more precisely:
Imaging, Klinikum at the University of Cologne (MEK),
4. to optimise hardware and software technologies for the integration Germany
of radiotracer, magnetic resonance and optical imaging data. This
Department of Endocrinology and Metabolic Diseases,
will require specific instrumental development and validation for
Leiden University Medical Centre, The Netherlands
cancer research, as well as software tools for the co-registration,
quantitation and processing of multimodal data Centre of Excellence on Neurodegenerative Diseases,
Universit degli Studi di Milano, Milan, Italy
5. to develop so called smart imaging probes which are specific for
a given molecular process and which can be detected and localised Biospace Mesures, Paris, France
by at least one imaging modality
Department of Biomedical Sciences and Dept Physics -
6. to use further developments of mouse models of human cancer RUCA - Bio-Imaging Lab, Universiteit Antwerpen, Belgium
to: (i) improve the early detection of small cancers by advanced

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CANCER
MPI for Neurological Research, MRI Laboratory, Max MR Solution Ltd, Guildford, United Kingdom
Planck Society, Cologne, Germany
Wolfson Molecular Imaging Centre,Academic Dept of
CNRS- ICSN, Gif sur Yvette, France Radiation Oncology,The Victoria University of Manchester,
INSERM,ADR de Lyon, France United Kingdom
Dept. of Medical Biochemistry and Genetics,The Panum Gastroenterology Department, Hospital Clinic Provincial
Institute, University of Copenhagen, Faculty of Health, de Barcelona, Spain
Denmark Department of Dermatology and Rudolf-Virchow, Centre
Department of Biological Chemistry, Group of for Experimental Biomedicine, Julius-Maximilians-Universitt
Oligonucleotides, IOCB-AS of the Czech Republic Wrzburg, Germany
Lab. of Oncogene Regulation, Institute of CarcinoGenesis, Dept. of Radiology, Stichting Katholieke Universiteit,
Moscow, Russian Federation University Medical Centre Nijmegen, The Netherlands
Dept. of Organic Chemistry - NMR Laboratory, University Department Ingenieria Electronica / E.T.S.I.
of Mons-Hainaut, Belgium Telecomunication, Universidad Politcnica de Madrid, Spain
Laboratory de Mthodologie RMN, Fac des Sciences, Department of Urology & Department of Clinical
Universit Henri Poincar, Nancy, France Research, Faculty of Medicine, University of Bern,
Switzerland
Facult des Sciences de Base (FSB), Institut de Chimie
Molculaire et Biologique (ICMB) LCIB, Ecole Department of Physics "E. Fermi", University of Pisa, Italy
Polytechnique Fdrale de Lausanne, Switzerland ForschungsZentrum Juelich GmbH, Zentrallabor fur
Department of Radiopathology & Medical Isotope Use, Elektronik (ZEL), Juelich, Germany
NCPH-National "FJC" Research Institute for Radiobiology Department of Biochemistry, University of Cambridge,
& Radiohygiene, Budapest, Hungary United Kingdom
Institute of Nuclear Chemistry, University of Mainz, Centro Ciclotrone PET, Fondazione Centro San Raffaele
Germany del Monte Tabor, Milan, Italy
Coordination & Radiochemistry, Universit de Lige, Medres Medical Research GmbH iGR, Cologne, Germany
Belgium
Department of Nuclear Medicine, Radiochemistry &
Laboratory of Bioinorganic Chemistry & Biomedical NMR, Radiopharmaceutical,Technical University, Munich, Germany
Department of Biochemistry, Centro de Neurocincias de
Coimbra e Biologia Celular, Coimbra, Portugal
BRACCO Imaging S.P.A., Milan, Italy Acronym: EMIL
Radiology & Radiological Chemistry Division, University of EC contribution: 5 800 000
Basel, Switzerland Duration: 60 months
Consiglio Nazionale delle Ricerche, Istituto di Biostrutture Starting date: 01/07/2004
e Bioimmagini, Naples, Italy
Department of Inorganic Chemistry, Prague, Czech
Republic
Chemistry Laboratory, Durham University, United Kingdom
Laboratory of Applied Organic Chemistry and Catalysis,
Technische Universiteit Delft, The Netherlands
Dept. of Inorganic and Analytical Chemistry, Laboratory of
Rare Earths, University of Debrecen, Hungary
Radiopharmaceutical Chemistry Laboratory, Deutsches
KrebsForschungsZentrum Heidelberg, Germany
SKYSCAN, Aartselaar, Belgium
Mauna Kea Technologies, Paris, France

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CANCER TRANSFOG
Translational and functional onco-genomics: from

cancer-oriented genomic screenings to new diagnostic
tools and improved cancer treatment
Summary IV. Development of tools for diagnostic validation of molecular
signatures for cancers of high population impact,namely:colon,breast
The TRANSFOG project aims at the systematic identification and and lung. This will enable translation into clinical use of signatures
functional characterization of novel cancer genes with high potential obtained through the cancer-oriented genomic screenings performed
diagnostic and therapeutic value in breast, colon and lung cancer. by the participating units.In particular,the project is expected to define
The TRANSFOG partners will bring together world recognised and validate prognostic signatures associated with the tendency of
competences and resources to reach the following, integrated the above mentioned cancers to give rise to metastasis.
research objectives:
V. Establishment of a shared bioinformatic platform for functional onco-
I. Identification of novel cancer-related genes of high clinical- genomics data handling and standardisation.This will require a concerted
diagnostic potential, with a specific focus on progression and effort towards codification of the various biological assays according to
metastasis of colon, breast, lung cancer.This will be achieved mainly specific functional features analysed by each assay,using for example the
through extensive gene expression profiling of tumour/metastasis Gene Ontology as a template (www.geneontology.org),and the sharing
samples and of cell-based models of cancer progression.To extend of analysis software and tools.Towards the same aim, a web-accessible
the exploration range, differential proteomics and epigenetic analysis platform based on the Distributed Annotation System (www.biodas.org)
are also planned. The foreseen outcome is a ranked list of novel will be implemented.
candidate cancer genes emerging from integration of the screening
The TRANSFOG project will deliver a consistent and integrated
results, that will undergo functional characterisation and/or
amount of functional data on genes of as yet unknown activity and
diagnostic validation.
biological role. In the process of reaching this objective, the
II. Set-up of technologies for systematic cancer gene functional participating units will be enabled to set up truly post-genomic efforts
analysis and for identification of new molecular targets. Gene toward systematic gene functional characterisation.New technologies
functional analysis will be enabled by assembling collections of full- will be developed that will allow exploration of gene regulatory
length cDNAs (FL-cDNAs) and of short interfering RNAs (siRNAs) networks,protein-protein interactions and high-throughput cell-based
subcloned in expression plasmids, to assess the consequences of evaluation of basic biological functions such as motility, growth,
gene gain-or loss-of-function in cell-based and preclinical models. apoptosis, invasion, adhesion, polarisation and more complex
III. Systematic exploration of oncogenic/antioncogenic signalling processes as in vitro epithelial morphogenesis and angiogenesis.The
pathways, epigenetic regulatory mechanisms.Taking advantage of the technologies for systematic gene functional characterisation
FL-cDNA and siRNA collections made available by the project, cell- developed here will be useful for functional studies involving a variety
based experimental systems to study protein-protein interaction, of physiological and pathological processes, and will be made available
reporter gene expression and epigenetic modifications will be to the scientific community in the frame of a collaborative research
exploited for systematic analysis of the candidate genes. This will network.The bioinformatic networking endowed with the project will
result in datasets of protein-protein interaction, transcriptional and enable participating units to share tools for data handling, database
epigenetic regulation allowing a comprehensive overview of the exploration and functional gene annotation. It will also facilitate
alterations in signalling and regulatory networks involved in cancer integration of the present network with other EC-funded networks
progression. and with the European and global post-genomic community.

176
CANCER
Research activities assays will reach an adequate throughput for studying all identified
candidates, while other assays, exploring more complex processes,
To reach the proposed goals, TRANSFOG is structured in seven will most likely require additional candidate prioritisation. Large-
research activities, here briefly outlined. scale siRNA analysis will also be carried out on Drosophila cells to
identify genes relevant to cell motility. Mouse transgenic and
1. Cancer-oriented genomic screenings in tumours and cell lines
knockout approaches will provide information on the in vivo role of
Genome-wide screenings by DNA microarrays, array-CGH, epigenetic the identified candidates in cancer progression and provide the final
and proteomics will be carried out on tumour samples selected for validation of new molecular targets for cancer therapy.
metastatic progression of breast, colon and lung carcinomas, as well as
5. Proteomic approaches to the study of signal transduction and protein-
on cancer-oriented experimental models,like serine and tyrosine kinase
protein interactions
receptor-driven transcriptional responses,ligand-induced in vitro epithelial
morphogenesis and invasive growth, in vitro angiogenesis of endothelial Protein-protein interactions play a key role in a wide range of
cells.The results of the screenings will be integrated to generate a wide biological processes related to cancer progression. TRANSFOG
panel of previously uncharacterised genes that are potentially involved partners will set up procedures for high-throughput analysis of
in basic biological functions underlying cancer progression, such as cell multiprotein complexes by mass spectrometry, protein microarrays,
growth, apoptosis, motility, invasion, morphogenesis and others. Biacore biosensor analysis and cell-based protein-protein interaction
systems. Some of these procedures will take advantage of the FL-
2. Development of enabling technologies for systematic gene gain-of-
cDNA collection, which will provide the basis for highly parallel
function
protein synthesis and purification.
Among the possible approaches to functional characterisation of
6. Preliminary diagnostic validation of molecular cancer signatures
candidate genes identified by Activity 1, one is based on enabling the
expression of their full-length (FL)-cDNAs in cells of interest or in Converting a molecular signature emerged from a cancer genomic
bacteria for recombinant protein production. This will require the screening into a validated tool for clinical use is a demanding task.
assembly of a core FL-cDNA collection, which is a strategic delivery For instance, the platform originally used to define the signature (e.g.
of TRANSFOG. a certain type of microarray) may not be the most adequate for
subsequent capillary diffusion of the signature assay.A translational
3. Generation of a siRNA vector collection to enable systematic gene loss-
research phase is therefore required in which the signature of
of-function analysis
interest is re-assessed on new tumour samples and with other
A second way to analyse the function of genes is by inducing loss- platforms (e.g. realtime PCR, tissue microarrays,
of-function. This can be achieved also in mammalian cells by RNA immunohistochemistry), and cross-comparisons are made between
silencing technologies (Science 296:550-553, 2002). Some of the platforms available at different sites. Standardised procedure will be
participating groups have already set up these technologies. This defined for the various platforms, and for the management of data
know-how will be exploited for a key effort of the present project, of both clinical and experimental nature. The main diagnostic
that is the generation of a shared collection of thousands of human problem that the TRANSFOG project plans to address is the
siRNA constructs in a plasmid/retroviral expression system (which prediction of the probability with which a primary carcinoma of the
allows easy further transfer of the construct in the target cells of colon, lung and breast will give rise to metastasis.
choice), mainly targeting genes of unknown function that gain high 7. Generation of a common platform for data handling and gene functional
priority for TRANSFOG partners through their cancer-oriented annotation
genomic explorations described in Activity 1.The use of single-gene
silencing RNA species will allow the identification of individual gene Efficient handling and sharing of genomic profiles and gene functional
functions whereas combinatorial approaches will allow the annotation will be achieved by development of an integrated, web-
characterisation of polypeptides active in the same cellular pathways. accessible data handling system with annotation tools for analysis
of gene expression and function.The partner EMBL-EBI will provide
4. Development of high-throughput functional assays the necessary expertise in collaboration with bioinformatic
Many of the participants have previously developed and employed personnel of the other partners.
simple assays on cultured cells to evaluate growth, motility, survival,
invasion, adhesion, morphogenesis, transformation, angiogenesis and
other basic biological functions altered during tumour progression
and metastasis.
Modulation of these functions by the candidate genes will be
assessed by systematic transduction of cultured cells with FL-cDNAs
or siRNAs subcloned in expression vectors. Some of the proposed

177
CANCER
Coordinator
Prof. Storme, Guy
GEIE-LINC (Groupement Europen dIntrt Economique
- Liaison Network for Cancer)
c/o AZ-VUB Cancer Centre
Laarbeeklaan 101
1090 Brussels, Belgium
Phone: + 32 2 477 61 47
Fax: + 32 2 477 62 12
Project web-site: http://transfog.org
Prof. Medico, Enzio
The Oncogenomics Center
Institute for Cancer Research and Treatment S.P.
142 km 3.95
10060 Candiolo (TO), Italy
Phone: + 39 011 993 3234
Fax: + 39 011 993 3225
E-mail: enzo.medico@ircc.it
Keywords: Oncology, Genomics, Proteomics.
Partners
CNIO, Spain
DKFZ, Germany
NKI,The Netherlands
IRCC, Italy
UMCU,The Netherlands
IFOM, Italy
EMBL-EBI, United Kingdom.
Acronym: TRANSFOG
Duration: 48 months

178
FIRST CANCER
Further improvement of radiotherapy of cancer

through side-effect reduction by application
of adult stem cell therapy
Summary
Radiotherapy is the second most important
treatment modality after surgery in the
treatment of cancer.At present over 50% of
all cancer patients receive radiotherapy at
one stage in their course. Inevitably normal
tissues are also exposed to ionising radiation
during radiotherapy of tumours. This can
result in organ failure and hence can
seriously limit the treatment dose.
Reduction of the side-effects of
radiotherapy will not only increase the
quality of life after the treatment but may
also result in increased survival of cancer
patients as it will allow dose escalation to The FIRST project consists of two blocks of works (BOW). In BOW1 normal tissue radiobiol-
ogists are brought together to use established animal models to study the effects of cell
the tumour. This is true even if the most
therapy after radiotherapy.The cell therapy protocols are delivered by stem cell biologist
optimal physical dose delivery (conformal working in BOW2.
therapy, protons) of radiation is applied.
Radiation-induced organ failure is mainly
caused by stem cell sterilisation, leading to
a reduced reconstitution of functional cells.The innovative vision of marrow.However,tissue specific cells are only available in small numbers.
Therefore, bone marrow stem cells have the largest clinical potential
this project is to reduce radiation-induced complications through to be used for transplantation into irradiated organisms or individual
stem cell therapy. Replenishment of the depleted stem cell normal tissues to provide the organ with sufficient numbers of cells
compartment should allow regeneration of irradiated tissues. A necessary for regeneration.
successful replacement of stem cells and subsequent amelioration
of radiation-induced complications may open the road to completely Aim
new strategies in radiotherapy and help combat cancer. The aim of the project is to develop and optimise techniques to
prevent radiation-induced normal tissue complications using adult
stem cell therapy. The tissues of interest will be oral mucosa, skin,
Problem gut and salivary gland tissues.The first step will be to provide proof
Many attempts have been made to attenuate radiation-induced damage of principle for the impact of stem cells on the repair of irradiated
to normal tissues.Although much knowledge has been obtained on the tissues.
mechanism of radiosensitivity of normal tissue, and the pathogenic To this end protocols for the isolation, mobilisation, and
pathways that eventually result in loss of function, the vast majority of characterisation of bone marrow derived stem cells will be
remedies are either inadequate,diminish in time or have not been shown performed and developed. Specific targeted approaches for
to be selective for normal tissue only. Therefore a completely new transplantation of bone marrow derived stem cells will be designed
approach is needed. Today bone marrow transplantation is common and tested.
clinical practice. Due to new scientific knowledge and biotechnological
developments,only recently it has become apparent that bone marrow
transplantation may rescue other organs. Moreover, cells from certain
tissues may even repopulate the haematopoietic system.Similar findings
have been reported for stem cells derived from other tissues than bone

179
CANCER
Expected results: Potential applications:

1. optimised protocols for isolation, generation, mobilisation, The resulting scientific and (bio)technological knowledge and a successful
characterisation and expansion of stem cells from bone marrow replacement of stem cells and subsequent amelioration of radiation-
induced complications may eventually lead to new and improved cancer
2. demonstration of proof of principle for the use of bone marrow- treatment strategies which will profoundly increase radiotherapy
derived stem cells to modificate radiation-induced normal tissue treatment success.
damage in animal models.
The blocks of work (BOW) are divided into workpackages (wp).Workpackage 1-4 are the normal tissues studied.They use together with
other partners the methods described to determine the success of transplantation.WP 5-8 concerns the different stem cell types and pro-
tocols, common techniques are shared and are distributed to BOW1.TUD (P5): Medical Faculty Carl Gustav Carus, Radiobiology Laboratory,
Prof. Dr.Wolfgang Drr (D). CEA (P3): CEA- Service de Gnomique Fonctionnelle, Dr. Michle Martin (F). University of Groningen, RSCB (P1)
Radiation and Stress Cell Biology, Dr. Robert Coppes (Co-ordinator, NL), IRSN (P3) IRSN, Dpartement de Radioprotection de la Sante de
l'Homme et de Dosimetrie, Dr. Dominique Thierry (F). SCB (P2), University of Groningen, Stem Cell Biology Prof. Dr. Gerald de Haan (NL),
LH (P7) Universit Franois Rabelais, Facult de Mdecine, Laboratoire d'Hmatopose. Dr. Pierre Charbord (F). 7TM, 7TM Pharma A/S,
Hrsholm, Prof. Dr.Thue Schwartz (DK).

180
CANCER
Coordinator
Dr Coppes, Rob
Department of Radiation and Stress Cell Biology
Faculty of Medical Sciences
University of Groningen
A. Deusinglaan 1
9713 AV Groningen,The Netherlands
Phone: + 31 50 3632709
Fax: + 31 50 3632913
E-mail: r.p.coppes@med.rug.nl
Project web-site:
http://www.rug.nl/med/onderzoek/internationalepro-
jecten/europeseprojecten/first (in preparation)
Key words: radiation-induced complications, adult stem
cell therapy, cancer therapy
Acronym: FIRST
Duration: 24 months

181
CANCER CANCERDEGRADOME
Extracellular proteases and the cancer degradome:

Innovative diagnostic markers, therapeutic targets
and tumour imaging agents
Summary
Extracellular proteases have complex roles with distinct functions at
different stages of tumour development and progression,and may have
conflicting effects on malignancy. The complete repertoire of
extracellular proteases through which cells regulate their local
environment is termed the Degradome. Extracellular proteases
remain an attractive target for intervention against cancer and we
propose to transfer recent insights into their function to pre-clinical
and clinical settings.
Problem
The critical defining feature of a malignant tumour is the presence of
cells that have broken through tissue boundaries and penetrated into
surrounding normal tissues. It has long been recognised that cellular
invasion of basement membranes and connective tissue stroma
involves the actions of diverse extracellular proteases from multiple
enzymatic classes, including the metalloproteinases (MPs) and the
serine,threonine,thiol and aspartic proteases,which can be produced
either by cancer cells themselves or by neighbouring host cells.These
cellular proteases participate also in the formation of new blood
vessels that support the burgeoning energy demands of a rapidly
growing tumour, and in the ability of cancer cells to metastasize to
distant organs. They constitute the Degradome the complete
repertoire of proteases that cells and tissues coordinatively regulate 3) Cellular proteases are target molecules for improving tumour
in order to modulate their local environment. detection and imaging.
We now understand that pericellular proteolysis is important in the The goals in molecular diagnostics are to develop molecular profiling
regulation of: technologies and markers of disease status that are broadly applicable
to the selection of patients for therapy, or to screening of disease-
1) growth factor activation, bioavailability and receptor signalling; free individuals who may benefit from prophylactic interventions.
2) cell adhesion and motility, 3) apoptosis and survival mechanisms;
4) angiogenesis; Aim
5) specification of cellular identity,and 6) inflammatory responses and The aim of this project is to define new molecular targets for drug
immune surveillance. design and to develop novel specific interventions that are based on
In the battle against cancer, the Degradome is important in three thorough knowledge of the pathophysiological roles of target
principal areas. proteases and related molecules, and to understand how and when
to use them. The identification of new molecular diagnostic and
1) Cellular proteases and their inhibitors are components of the prognostic indicators of patient risk, together with new ways to
molecular machinery of malignancy, and thus are attractive as enhance visualisation of tumours in the clinic,will improve health care
therapeutic targets. delivery based on an individualised, patient-oriented approach to
2) Degradome genes are valuable as prognostic and diagnostic cancer therapy.
markers of disease that can improve the accuracy of conventional
clinical and histopathological assessment.

182
CANCER
Expected results
1.The determination of Degradome gene expression patterns in
human tumour cell lines and mouse models.
2. A detailed analysis of Degradome gene function using tumour
prone mouse models.
3.The analysis of protease inhibitor function in combination with
other therapies.
4. Elucidation of the interplay between proteases and other key
molecules of intracellular and intercellular signalling.
5. Determination of the regulatory factors that control protease gene
expression in tumours and in the tumour-host dialogue.
6. Characterisation of the cellular expression of Degradome genes Potential applications
for breast and prostate cancer. Several major pharmaceutical companies have been involved in the
7. Development of active site-directed inhibitors of development of synthetic protease inhibitors for cancer therapy over
metalloproteinases. the past decade. However, the vast majority of trials have shown these
first generation compounds to have limited effects.What is now clear
8. Development of ligands able to prevent the formation of protease- is that the biological activities of extracellular proteases,and their roles
substrate, protease-inhibitor, protease-receptor complexes. in normal and diseased tissues, are much more complex than was
9. Production of radiotracers for protease ligands for in vivo imaging, originally envisioned.The original notion of proteases solely as mediators
with transfer to clinical paradigms. of pathological tissue destruction is an oversimplification: in fact, some
proteases have functions that inhibit tumour development and
progression, and moreover, their natural inhibitors (TIMPs, PAIs, etc)
can in some instances enhance tumourigenesis. The identification of
protease targets for the design of novel and specific interventions will
offer improvements for health care delivery and patient management.
The knowledge obtained in this project can also be used to identify
cancer susceptibility in otherwise healthy individuals.
Overview of rat, mouse, and human degradomes.This figure

represents the complete set of protease and protease homologue
genes from the indicated species.

183
CANCER
Coordinator Faculty of Chemistry, National and Kapodistrian

Prof. Edwards, Dylan University of Athens, Greece
School of Biological Sciences Ecole Polytechnique Federale de Lausanne, Switzerland
University of East Anglia Institut fr Molekulare Medizin und Zellforschung,

Freiburg, Germany
Norwich NR4 7TJ, United Kingsom
Dept of Genetic Toxicology, National Institute of Biology,
Phone:+ 44 1603 592184 Ljubljana, Slovenia
Fax: + 44 1603 593222 Mario Negri Institute for Pharmacological Research,
E-mail: dylan.edwards@uea.ac.uk Bergamo, Italy
Project web-site: http://www.cancerdegradome.org/ Humboldt University, Berlin, Germany
Key words: cancer, metalloproteinase, protease, metas- Division of Cardiovascular and Medical Sciences,
tasis, diagnostics, tumour imaging University of Glasgow, United Kingdom
Institut de Genetique et de Biologie Moleculaire et
Cellulaire, Illkirch, France
Partners
Institut fur Experimentelle Onkologie und
The Finsen Laboratory, Copenhagen University Hospital, Therapieforschung,Technical University of Munich,
Denmark Germany
IFOM Institute of Molecular Oncology, Milan, Italy Proteros Biostructures GmbH, Martinsried, Germany
CRCE Faculty of Medicine, University of Lige, Belgium Division of Carcinogenesis and Differentiation, Deutsches
Dpto de Bioquimica y Biologia Molecular, Universidad de Krebsforschungszentrum, Heidelberg, Germany
Oviedo, Spain Dept of Molecular Biology, University of Aarhus,
Cambridge Institute of Medical Research, University of Denmark
Cambridge, United Kingdom Institute of Genetics and Biophysics Adriano Buzzati-
Dept Medical Biochemistry and Biophysics, Karolinska Traverso, Naples, Italy
Institute, Stockholm, Sweden Istituto di Endocrinologia e Oncologia Sperimentale G.
Departement d-Ingenierie et deEtudes des Proteines, Salvatore, Naples, Italy
Gif-sur-Yvette, France Institut de Biologia Molecular de Barcelona, Spain
Unit d'Imagerie de l'Expression des Genes, Orsay, University of Southampton Human Genetics Division,
France School of Medicine, United Kingdom
Laboratory for Experimental Oncology, Department of OncoMethylome Sciences SA, Lige, Belgium
Medical Oncology, University Hospital Gasthuisberg,
Leuven, Belgium Genoptics SA, Orsay, France
Centre for Biotechnology,Turku, Finland Laboratory for Radiopharmacy, University of Ghent,
Belgium
VTT Medical Biotechnology Group,Turku, Finland
KRKA, Department of Biochemical Research and Drug
Dept. of Vascular Biology & Thrombosis Research, Design, Lujbljana, Slovenia
University of Vienna, Austria
Institute of Pathology, Cantonal Hospital, University of
Max Planck Institute for Biochemistry, Planegg- Basel, Switzerland
Martinsried, Germany
Acronym: CANCERDEGRADOME
Duration: 48 months

184
STROMA CANCER
Selective targeting of angiogenesis and

of tumor stroma
Summary European Network in research and in the pharmaceutical development
of ligand-based,targeted anti-cancer therapies,with a particular emphasis
Targeted delivery of therapeutic agents to the tumor microenvironment on the targeting of tumor neo-vasculature and tumor stroma.
is a novel avenue for cancer treatment toward the development of more This project focuses on the:
efficacious and better-tolerated anticancer drugs. - Identification and validation of molecular targets which are
selectively expressed in the stroma and in neo-vascular sites of
This project aims to identify new molecular targets which are selectively aggressive solid tumors. Endothelial cells and stromal cells are
expressed in tumor stroma and in the neo-vasculature of aggressive genetically more stable than tumor cells and can produce abundant
tumors and to develop new therapeutic strategies based on high affinity markers, which are ideally suited for tumor targeting strategies.
binding molecules capable of selective localization in tumor stroma - Isolation of high-affinity binding molecules [small organic compounds,
and/or vascular structures. Efforts to move the most promising antibodies], which are specific for markers of angiogenesis and/or
the tumor stroma, and are capable of selective localization in the
product(s) generated within this Integrated Project into Clinical Trials tumor environment, after intravenous administration.
is the ultimate scope of the project.
- Development of therapeutic strategies, based on specific binding
Potential application is the pharmacological treatment of solid molecules capable of selective localization around tumor vascular
structures and/or in the tumor stroma.
neoplasms, maintaining or improving present percentage of
- Dissemination of the research activities of the Project.
respondents, survival, disease-free interval, with improved safety and a
better quality of life.
Expected results
Problem
The majority of pharmacological approaches for the treatment of solid
tumors suffers from poor selectivity, thus limiting dose escalation (i.e.,
the doses of drug which are required to kill tumor cells cause
unacceptable toxicities to normal tissues).The situation is made more
dramatic by the fact that the majority of anticancer drugs accumulate
preferentially in normal tissues rather than in neoplastic sites,due to the
irregular vasculature and to the high interstitial pressure of solid tumors.
One avenue towards the development of more efficacious and better
tolerated anti-cancer drugs relies on the targeted delivery of therapeutic
agents to the tumor environment, thus sparing normal tissues.
This experimental strategy requires a range of diverse experimental
techniques, for the identification of targets, for the isolation of binding
molecules, and for their conversion into imaging and therapeutic
products. Our approach has the potential advantage that immuno-
histochemistry, imaging and biodistribution data provide information
about the selectivity of the anti-cancer drugs at several stages of the Flow-chart, outlining the main expected results, leading from target
drug development process,and allow a rational optimization of the most identification to the development of novel anticancer therapeutics.
promising lead compounds.
Aim We will consider the project as fully successful if at least one molecule
In the past,our Consortium has developed innovative anti-cancer imaging enters clinical development for pharmacological treatment of solid
and therapeutic strategies, based on recombinant antibody fragments, neoplasms, maintaning or improving present percentage of res-
which have moved from the bench to the clinic. With the STROMA pondents, survival, disease-free interval, with improved safety and
Project, we plan to strengthen and extend a leading position of our better quality of life.

185
CANCER
Prof. Castronovo,Vincent
Coordinator
Facult de Mdecine
Dr Giavazzi, Raffaella
Laboratoire de Recherche sur les Metastases
Laboratory of the Biology and Treatment of Metastasis
Universit de Lige
Department of Oncology
Lige, Belgium
Istituto di Ricerche Farmacologiche Mario Negri
Prof. van Dongen, Guus
Via Gavazzeni 11 Laboratory for Tumour Biology
24125 Bergamo, Italy Department of Otolaryngology
Phone: + 39 035 319888 VU University Medical Center,
Fax: + 39 035 319331 Amsterdam,The Netherlands
E-mail: giavazzi@marionegri.it Dr Zanda, Matteo
Project web-site: Istituto di Chimica del Riconoscimento Molecolare,
http://www.esh.org/DEFAULT/STROMA/sconsortium.htm Consiglio Nazionale delle Ricerche
Key words: neoplasm, stroma, angiogenesis, selective Milan, Italy
targeting, combination therapy, antibody,
Dr Vajkoczy, Peter
small molecules, oncofetal antigens,
tumour neo-vasculature Faculty for Clinical Medicine Mannheim
Department of Neurosurgery
Ruprecht-Karls-Universitt Heidelberg
Partners Mannheim, Germany
Prof. Bikfalvi, Andreas
Prof. Kosmehl, Hartwig
Molecular Mechanisms of Angiogenesis Laboratory
Institute of Pathology
INSERM E 0113
Helios Klinikum Erfurt GmbH
Institut National de la Sant et de la Recherche Medicale
Erfurt, Germany
Universit Bordeaux 1
Dr Dinkelborg, Ludger
Talence, France
Radiopharmaceuticals Research
Dr Bicknell, Roy
Schering AG
Molecular Angiogenesis Laboratory
Berlin, Germany
Cancer Research UK, Institute of Molecular Medicine
Dr Viti, Francesca
University of Oxford
Philogen s.r.l.
John Radcliffe Hospital
Siena, Italy
Dr Umaa, Pablo
Prof. Neri, Dario
Glycart biotechnology AG,Wagistrasse 18
Institute of Pharmaceutical Sciences
Zurich, Switzerland
Swiss Federal Institute of Technology
Dr Marsoni, Silvia
ETH Hnggerberg
Sendo Foundation
Zurich, Switzerland
Milan, Italy
Prof. Begent, Richard
Dr Jasmin, Didi
Royal Free Campus
European School of Haematology
Department of Oncology
Centre Hayem, Hpital Saint Louis
Paris, France
Prof. Zardi, Luciano
Istituto Giannina Gaslini Acronym: STROMA
Centro di Biotecnologie Avanzate, Project number: LSHC-CT-2003-503233
Istituto Nazionale per la Ricerca sul Cancro Instrument: Integrated Project
Genova, Italy Duration: 48 months

186
Mutp53 CANCER
Mutant P53 as a target for improved

cancer treatment
Summary
Mutations in the p53 tumour suppressor gene are the most frequent
genetic alteration in human cancer, occurring in over 40% of all cases
of cancer. One well-studied outcome of these mutations is the loss of
the tumour suppressor activity of the wild type (wt) p53.However,there
is growing evidence that many of the mutations that occur in the p53
protein generate mutant p53 proteins (mutp53) have acquired new
biochemical and biological properties. Through this gain of function
(GOF),mutp53 is believed to contribute actively to the cancer process.
We propose to explore mutp53 as a target for novel anti-cancer

therapies. Such therapies should aim to either abrogate the GOF effects
of mutp53, or restore wt-like properties to mutp53, so that it can now
regain its tumour suppressor capabilities. A multi-disciplinary approach
will be undertaken to explore and exploit the contribution of mutp53
to cancer.
The p53 tumor suppressor pathway. p53 is normally an unstable
One component of this project will investigate in depth the molecular
protein but becomes stabilized in response to various forms of cel-
properties of mutp53: structural studies will pinpoint the changes that lular stress, e.g. DNA damage, oncogenic singalling and hypoxia.
particular mutations inflict on the structure of p53, and allow the The accumulation of p53 protein triggers cell cycle arrest, apopto-
classification of mutp53 into distinct subclasses. In parallel, biochemical sis and/or senescence.
studies will explore the mode of action of mutp53 within cells,including
its impact on patterns of gene expression,identification of specific DNA
sequences targeted by mutp53, and discovery of mutp53-interacting
cellular proteins. Preclinical models for mutp53-driven cancer will also
Problem
be developed, as a critical instrument for pre-clinical studies. Cancer is a major cause for human suffering in Europe as well as
elsewhere in the world. It causes immense effects on the cancer
The other component will aim at translating this wealth of information patients themselves, on their families, as well as on society at large.
into better cancer therapy.One avenue will address the clinical relevance In additional to the severe human suffering and their immediate
societal impact, cancer treatment and management is also a major
of particular p53 mutations in human cancer, particularly its impact on economic burden.The importance of this problem and the urgency
the patients response to chemotherapy.This should lead to guidelines of the need for novel approaches to cancer management and
for more effective use of conventional therapy.The other avenue will treatment have been recognised by the EC, as reflected by the
establishment of a specific call in the area of Combating Cancer.
explore novel therapies targeted at mutp53 and mutp53-expressing
Mutations in the p53 tumour suppressor gene are the most frequent
tumour cells. A major effort will focus on the discovery of small
genetic alteration in human cancer, occurring in over 40% of all cases
compounds that can restore wtp53-like activity to mutp53.An innovative of cancer.We propose to explore mutp53 as a target for novel anti-
approach to immunotherapy directed against mutp53-overexpressing cancer therapies. Such therapies should aim to either abrogate the
cancer cells will also be explored.Owing to the extremely high frequency gain of function (GOF) effects of mutp53,or restore wt-like properties
to mutp53,so that it can now regain its tumour suppressor capabilities.
of p53 mutations, the success of this project will impact on a very large A multi-disciplinary approach will be undertaken to explore and
number of cancer patients in Europe and worldwide. exploit the contribution of mutp53 to cancer.

187
CANCER
Aim
In our proposed project, we introduce a multidisciplinary approach
to explore mutp53 as a new target for innovative treatment. p53 is a transcription
factor that binds spe-
A primary objective of the Combating Cancer initiative is to combat cific DNA motifs in
cancer by developing improved patient-oriented strategies to better p53 target genes and
treatment with minimal side-effects with a focus on encouraging the activates transcrip-
development of evidence-based guidelines for good clinical practice. tion.The consensus
Our project meets these requirements in at least two distinct ways: p53 binding motif is
RRRCWWGYYY N0-
1.We aim to improve the use of contemporary chemotherapy 13 RRRCWWGYYY
through providing better guidelines based on correlations between where R is purine,W
p53 genotype of the tumour and its response to particular types is A or T, and Y is
of anti-cancer drugs. pyrimidine.
It is important to keep in mind that, although novel therapeutic
approaches are very exciting and promising, millions of cancer
patients all over Europe are being treated every day with standard p53 missense muta-
chemotherapy.Beyond its limited efficacy,this is also associated with tions in human tumors
significant toxicity and therefore often unjustified patient suffering. cluster in the DNA-
The ability to make better predictions as to which particular binding core domain
chemotherapeutic regimen is most likely to work for a particular (approximately residues
patient thus has far-reaching implications, both in ensuring better 100-300). So called hot
and more effective treatment and,not less importantly,in preventing spots mutations include
unnecessary suffering from severe side-effects in cases where it is Arg248 and Arg273
clear that a particular treatment is not going to work.Providing new (DNA contact mutants)
recommendations to oncologists, allowing them to individualise and Arg175, Gly245,
the chemotherapy course chosen for a given patient, will therefore Arg249, and Arg282
meet the objective of better treatment with minimal side-effects, (structural mutants).
and will provide evidence-based guidelines for good clinical practice.
2.A major component of this project is aimed at developing novel
therapies, based on mutp53 knowledge to be gained by the 3. explore in depth the structural properties of selected mutp53 proteins,
consortium. in order to provide leads for structure-based rational drug design;
The increased selectivity and specificity of such drugs is most likely 4. evaluate the impact of mutp53 status on the response of selected
types of human tumours to chemotherapy,and use this information
to reduce side-effects on normal patient tissue, because such tissue
to formulate guidelines for more effective use of currently available
does not express any mutp53,unlike the targeted tumour cells.Thus,
anti-cancer therapies;
any successful drug that comes out of this project is highly likely to
lead to improved clinical practice and to better treatment, with 5. search for molecules and compounds that can selectively interfere
reduced side-effects as compared to the presently available options. with mutp53 GOF or restore wtp53 activity to mutp53,and explore
Moreover, the fact that close to half of all human tumours possess them as potential anti-cancer drugs;.
mutp53 in abundant amounts makes any new drug emanating from
6. initiate clinical trials (Phase I) with one mutp53-selective drug that
this endeavour potentially valuable to a very large number of cancer
has already gone successfully through pre-clinical studies;
patients.Such drug,if successful,may thus have far-reaching impacts,
not only on individual cancer patients, but also on European society 7. generate leads and new tools towards the development of mutp53-
as a whole. based immunotherapy.
Expected results
The proposed project will address the following main objectives:
1. elucidate the biochemical basis for mutp53 GOF (GOF),with special
emphasis on genomics and proteomics approaches;
2. evaluate the contribution of mutp53 to the malignant properties
of cancer cells;

188
CANCER
Potential applications Mutant p53 reac-

Cancer represents one of the most severe health problems in the tivation as a novel
European community. Cases are growing with the age of the strategy for cancer
population. The economic and emotional burden is enormous. therapy.
Mutp53 protein is expressed in about 50% of all human tumours. Restoration of wild
In some categories with growing incidence, e.g. lung cancer, colon type conformation
carcinoma and skin tumours, more than 60-70% of the tumours are and function to
associated with mutated p53.This may be due to the induction of abundant mutant
p53 mutations by dietary and environmental carcinogenic insults, p53 by a novel
which are encouraged by modern western societys lifestyle (expo- drug triggers mas-
sure to sun,very heavy smoking in most parts of Europe,high-fat diet). sive apoptosis and
thus eliminates
In some types of cancer, expression of mutp53 appears to be
the tumor.
particularly highly correlated with the more aggressive tumour
stages.Yet, in many cancers, mutation of p53 appears to occur during
the very early steps of carcinogenesis.This is particularly true for An effective novel treatment of cancers expressing mutp53 could
cancers of the lung, head-and-neck, bladder, skin and oesophagus. help to prolong life expectancy and quality of life. Such a treatment
In these pathologies, mutp53 is amongst the earliest tumourigenic may be applicable for eradicating small lesions in pathologies where
changes that can be detected in the patient, sometimes ahead of mutation is an early event, thus providing low-cost, low-stress
the clinical diagnosis of a cancer lesion.The expression of mutp53 approaches for lesions that are currently managed through surgery
is relatively easy to diagnose, employing immunohistochemical and/or chemotherapy. On the other hand, mutp53-based therapies
assays that are already available as commercial kits and are in use can be applied synergistically with conventional therapy regimens
in many pathology laboratories throughout Europe. However, there in patients with advanced cancers.The mutp53-based approach thus
opens a whole range of possibilities that can be implemented in
Mutant p53 gain-of- current medical practice without costly equipment, infrastructures
function.Wild type or extensive training programmes.
(wt) p53 binds spe- Development of effective anti-cancer therapy for mutp53-
cific DNA motifs expressing tumours would lower direct and indirect costs by
and activates p53 reduction of surgery and intensive care, reduction of duration of
target genes. medical survey, reduction of emotional burden for patients and their
Mutant p53 fails to family and faster reintegration of patients as part of the working
bind specific DNA economy. In addition, one should keep in mind that although novel
motifs and activate anti-cancer therapies are a very exciting avenue, millions of cancer
p53 target genes. patients in Europe are presently being treated with conventional
Putative gain-of- chemotherapy. Current chemotherapy has severe adverse effects
function activity of on the quality of life of the treated patient.The combination of data
mutant p53 may from experimental model systems and the cancer patient mutp53
include protein-pro- database might potentially identify groups of patients who are not
tein interactions and suitable for particular types of contemporary chemotherapy. Better
illegitimate activa- tools to decide which patients should be treated and which to be
tion of targets that left untreated are extremely important in reducing the suffering of
contribute to tumor those patients who will not benefit from the currently available
progression. cancer therapy modalities.
is still a lack of rapid, low-cost and sensitive assays for mutation

detection, and this is the key to the systematic implementation of
mutp53-based strategies for cancer diagnosis, prognosis, and
treatment.This is why one of the activities of our consortium will
be to support the validation and the transfer into production of a
new type of micro-array developed by Asperbio, an SME partner of
our consortium. Improved detection of p53 mutations may enable
earlier cancer diagnosis, increased curability and reduction in the
societal impact of cancer morbidity and mortality.

189
CANCER
Department of Chemistry, University of Cambridge,

Coordinator United Kingdom
Prof.Wiman, Klas International Agency for Research on Cancer (WHO),
Karolinska Institute Lyon, France
Department of Oncology-Pathology Department of Hematology & Oncology, Johannes-
Gutenberg-University Medical School, Mainz, Germany
Cancer Center Karolinska (CCK), R8:04
Department of Oncology-Pathology, Karolinska Hospital,
Karolinska Hospital Stockholm, Sweden
SE-171 76, Stockholm, Sweden Department of Molecular Cell Biology,The Weizmann
Phone: + 46 8 5177 9342 Institute of Science, Rehovot, Israel
Fax: + 46 8 32 10 47 Institute of Biophysics, Academy of Sciences of the Czech
Republic, Brno, Czech Republic
E-mail: Klas.Wiman@cck.ki.se
Laboratorio Oncogenesi Molecolare, Istituto Regina
Project web-site: www.mutp53.com Elena - CRS, Rome, Italy
Key words: p53 tumour suppressor, mutations, gain-of- Microbiology & Tumor Biology Center (MTC), Karolinska
function, p53 status, clinical outcome, mutant Institute, Stockholm, Sweden
p53-reactivating drugs, novel cancer therapy
Dept. of Structural Biology,The Weizmann Institute of
Science, Rehovot, Israel
Partners
Division of Molecular Biology H8,The Netherlands
Division of Tumor Biology,The Netherlands Cancer Cancer Institute, Amsterdam,The Netherlands
Institute, Amsterdam,The Netherlands
Johannes Gutenberg-University, Department of
Department of Cell Cycle & Cancer, Institute of Cancer Hematology and Oncology, Mainz, Germany
Biology, Copenhagen, Denmark
Asper Biotech,Tartu, Estonia
Molecular Oncogenesis Laboratory, Regina Elena Cancer
Center, Rome, Italy GanyMed, Mainz, Germany
Department of Genetics, Institute for Cancer Research, Aprea AB, Karolinska Institute, Stockholm, Sweden
Oslo, Norway
Laboratorio Nazionale CIB,Trieste, Italy
Acronym: Mutp53
Heinrich-Pette Institute, Hamburg, Germany Project number: LSHC-CT-2004-502983
Department of Physics of Complex Systems,The Instrument: Integrated Project
Weizmann Institute of Science, Rehovot, Israel Duration: 60 months

190
MOL CANCER MED CANCER
Developing molecular medicines

for cancer in the post-genome era
Summary to have evolved as a powerful protective barrier against cancer.
Immortalisation in vitro of normal human cells that lack telomerase
The cellular immortality enzyme telomerase (one of the most involves the reactivation of telomerase or, rarely, an alternative
(ALT) mechanism for maintaining telomeres. It is clear that
promising universal cancer markers) and associated telomere
telomerase is obligatory for continuous tumour cell proliferation,
maintenance mechanisms represent novel anti-cancer targets of clonal evolution and malignant progression. Because telomerase is
enormous therapeutic and diagnostic potential. In MOL CANCER found in around 90% of human cancers and is essential for the
continued proliferation (and clonal evolution) of cancer cells, it
MED, a multinational EU translational cancer research consortium has
represents one of the most exciting anti-cancer targets thus far
been established, in which expert cancer geneticists and molecular discovered. Results with a variety of telomerase inhibitory
biologists will interact with prominent pharmacologists, clinicians and strategies in human cancer cells have confirmed that its functional
pathologists to develop these exciting new cellular targets into inactivation results in progressive telomere shortening, leading to
growth arrest and/or cell death through apoptosis. Promising
measurable pre-clinical advances, within a four-year time-frame. candidate small molecule inhibitors are beginning to emerge that
will form the basis for anti-telomerase drug development. MOL
The project has been structured into three, highly interactive areas
CANCER MED is based on successful Framework 5 research
of activity, involving the fundamental evaluation and pre-clinical concerned with establishing the value of the cellular immortality
validation of: (i) telomerase as a target for cancer treatment and enzyme telomerase as an anti-cancer target (Project: QLG-1999-
diagnosis based on new molecular knowledge about its expression 01341;TACIT) and represents an expansion and elaboration of this.
TACIT yielded results that have triggered new translational research
and function, (ii) associated downstream telomere maintenance with clearly defined clinical applications.To this set of activities have
mechanisms as additional targets for novel drug design, and (iii) new been added carefully selected new EU research teams, notably in
anti-cancer drugs based on these targets.The consortium will bring the area of drug development.
to bear diverse and complementary technological know-how of
considerable power to deliver the above primary objectives. Effective Aim
management will maximise synergies across MOL CANCER MED in The principal aim of MOL CANCER MED is to fully exploit the
order to produce genuine improvements in the design of new results of recent fundamental advances in understanding the role
of telomerase and telomere maintenance mechanisms in human
treatments that promise to be active against a broad spectrum of
cancer development, in order to achieve genuine clinical benefit (i.e.
common human malignancies. in developing both improved diagnostics and anti-cancer therapies).
The principal measurable objectives of the project, over the
complete 48 month period, are: (i) to validate further the potential
Problem of telomerase and telomere maintenance systems in cancer therapy
Cancer is a leading cause of death in the western world, second only and diagnosis, (ii) to identify novel molecular targets based on
to cardiovascular disease, and is therefore a European public health
problem of overwhelming human and economic significance. The
incidence of cancer is set to increase substantially with demographic
and possibly environmental influences playing a part. However, there
is now an improved molecular understanding of the key genetic,
biochemical and cellular changes leading to cancer, in significant part
due to the efforts of diverse groups of world-class EU-based scientists.
With the completion of the human genome sequence imminent, it is
now timely to initiate a major European coordinated effort to translate (A) Normal human skin
fundamental scientific knowledge about cancer into safer, more (B) organotypic culture of the immortal HaCat skin keratinocytes
effective, therapies and improved early diagnostic procedures. Both are co-stained with an antibody against hTERT (red nuclear
staining) and an antibody decorating the basement membrane (green
MOL CANCER MED is focused on a single group of highly
staining). All nuclei are counterstained with DAPI (in blue)
promising anti-cancer targets associated with telomerase and
telomere maintenance. Repression of telomerase in the somatic
tissues of humans, and probably other long-lived mammals, appears

191
CANCER
telomere structure, function & stability, that may be of value in Potential applications
treatment and diagnosis of the common human cancers, (iii) to
create a programme of novel small molecule drug development The emphasis of the LIFESCIHEALTH Priority is very firmly placed
based initially on recently identified (but thus far poorly exploited) upon multidisciplinary translational research, in which fundamental
targets and, later (from month 12 onwards) exploiting completely scientific knowledge is harnessed for the specific purpose of
new targets identified during the project. generating, within the timeframe of FP6, reagents, treatments and
diagnostics that are of clinical value. In MOL CANCER MED, a highly
focused strategy will be adopted towards applying molecular genetic
Expected results knowledge about the mechanisms underlying the cancer process to
1. Novel anti-cancer drug targets and diagnostic methodologies the development of completely new approaches to cancer treatment,
derived from advances in: (i) the understanding and definition of eg in bringing molecular biology, cell biology, genomics and target
biochemical response pathways underpinning the telomere evaluation together with small molecule drug discovery.
checkpoint for somatic cell proliferation, (ii) the identification and
molecular/functional characterisation of natural mechanisms of
telomerase repression and cell self-renewal (including hTERT
repressor genes and chromatin remodelling factors) in normal
human cells and their dysregulation in human cancers, and (iii)
understanding the mechanisms of action and pharmacological
activity of existing small molecule telomerase inhibitors (eg
BIBR1532), and (iv) establishment of the precise roles of telomere
aggregates and telomere-length-independent functions of
telomerase in human cancer.
2. An advanced molecular understanding of telomerase regulation at
chromosome ends (eg involving the key telomere-binding proteins
POT1 and hEST1A) and a comprehensive evaluation of such
proteins as anti-telomerase drug targets
3. New and effective molecular inhibitors (eg siRNAs, ribozymes &
peptide nucleic acids) of telomerase and telomere maintenance Human Telomeres
(targeting hTERT transcription and telomere-related proteins
discovered within the MOL CANCER MED Consortium) for the
purpose of vasli.
4. Panels of new molecular markers of telomerase repression,
telomere maintenance and associated signalling pathways, that can
be developed into precise, rapid assays for use in novel kits for
early cancer diagnosis and prognostic evaluation.
5. An understanding of the differential effects of telomerase/telomere
maintenance inhibition on normal human tissues and in cancers
using organotypic in vitro human cell models.
6. Rational design of libraries of novel small molecule compounds for
screening against new targets, and selection of small molecule anti-
telomerase/telomere maintenance drug leads active against
individual new targets discovered during the course of MOL
CANCER MED.
7. Identification of potential anti-cancer drugs from the above,
following biochemical, pharmacological and functional (in vitro and
in vivo) anti-tumour assays.
8. Preclinical exploitation of potential novel cancer drugs through
interface with clinical oncology centres and SMEs.

192
CANCER
Dr Parkinson, Kenneth
Coordinator University of Glasgow
Prof. Newbold, Robert
Glasgow, United Kingdom
Brunel University
Dr Martens, Uwe
Kingston Lane
Medical University Center Freiburg
Uxbridge UB8 3PH, United Kingdom
Freiburg, Germany
Phone: + 44 1895 203090
Prof. Boukamp, Petra
E-mail: robert.newbold@brunel.ac.uk
DKFZ
Project web-site:
Heidelberg, Germany
www.brunel.ac.uk/research/molcancermed/
Dr Blasco, Maria
Key words: cancer, therapy, genome, telomerase,
diagnosis, drugs CNIO
Madrid, Spain
Partners Prof. Keith, Nicol
Prof. Neidle, Stephen University of Glasgow
London School of Pharmacy Glasgow, United Kingdom
London, United Kingdom Dr Zaffaroni, Nadia

National Cancer Institute
Dr Mergny, Jean-Louis
Milan, Italy
INSERM
Dr Serakinci, Nedime
Paris, France
University of Aarhus
Prof. Mann, John
Aarhus, Denmark
Queens University Belfast
Dr Roos, Goran
Belfast, United Kingdom
Umea University
Dr DIncalci, Maurizio
Umea, Sweden
Istituto de Richerche Mario Negri
Milan, Italy
Acronym: MOL CANCER MED
Dr Lingner, Joachim Project number: LSHC-CT-2004-502943
ISREC Instrument: Integrated Project
Epalinges, Switzerland Duration: 48 months

193
CANCER EUROXY
Targeting newly discovered oxygen-sensing cascades

for novel cancer treatments
Summary
The last decade's basic and clinical oncology research has revealed a
number of so far unrecognised regulating responses (e.g.HIF-1) in cells
Coordinator
Ebbesen, Peter
exposed to hypoxia. Laboratory of Stem Cell Research
Research Park
These processes have been proven to have a major impact on tumour
Gustav Wiedsvej 10
progression and resistance to radiotherapy and certain types of 8000 Aarhus C, Denmark
chemotherapy. Because of their strong over-expression in solid cancer Phone: + 45 86 12 73 66
tumours in comparison to adjacent normal tissue of these processes, Fax: + 45 86 19 54 15
E-mail: ebbesen@lsr.auc.dk
this new knowledge may open a therapeutic window for cancer
Key words: Biology Equipment, Drug Candidates, Hypoxia,
treatment by utilising hypoxia-responsive processes as drug targets. HIF-1, CA IX, Preclinical, Drug Development.
Over the first two to three years we will dissect relevant steps in cancer
cell response to hypoxia, develop a technology platform for in vitro Partners
AstraZeneca UK Limited, United Kingdom
control of oxygen tensions peri-cellularly, further identify and
Aventis Pharma, France
characterise marker/target molecules, and do the initial in vitro drug Institute of Biotechnology - Lithuania
development. Charit - Universittsmedizin Berlin, Campus Virchow
Klinikum, Germany
Our mid-term evaluation will then select which hypoxic processes may University of Zurich, Switzerland
be suitable as targets for cancer-specific treatment. Deutsches Herzzentrum Mnche, Klinik an der TU Mnchen,
Germany
Simultaneously, we will study diagnostic tagging and therapeutic Jobst Technologies GmbH, Germany
strategies leading up to a selection process of promising compounds Universiteit Maastricht / Research Institute GROW,
Maastricht,The Netherlands
to be further developed after the end of the project period. LEA Medizintechnik GmbH, Germany
The new treatments will be developed along two lines:targeting known Leo Pharma A/S, Denmark
Imperial College of Science,Technolgy and Medicine, United
cytostatics towards the newly discovered hypoxia-responsive molecules Kingdom
and searching for so far unused compounds, preferably toxic to Oxford BioMedica Plc, Oxford, United Kingdom
pathways active during hypoxia. Institute of Virology, Slovak Academy of Sciences, Slovakia
The University of Oslo, Norway
The consortiums final effort shall ensure industry use of our results. Karolinska Institutet, Sweden
The Chancellor, Masters and Scholars of the University of
Oxford, Oxford, United Kingdom
RiNA-Netzwerk RNA Technologien GmbH, Germany
University of Florence, Department of Chemistry, Florence,
Italy
The Victoria University of Manchester, Manchester, United
Kingdom
Albert Ludwigs University Freiburg, Freiburg, Germany
ViVoX ApS, Denmark
Acronym: EUROXY
Duration: 60 months

194
MAESTRO CANCER
Summary - adaptive radiation delivery, tracking and control for radiotherapy

(WP1),
- radiotherapy software development (WP2),
At the beginning of the third millennium one European citizen out of
- sensors for dose evaluation in radiotherapy (WP3),
three will have to deal with a cancer episode in the course of his/her - clinical requirements, protocols and validation (WP4),
life.Worldwide the estimated number of new cancer cases each year - organs at risk assessment studies (WP4),
is expected to rise from 10 million in 2000 to 15 million by 2020.Cancer - clinical workshops for training and dissemination purposes (WP5),
is currently the cause of 12% of all deaths worldwide. - management (WP6)
Within the European Union over 2 million new cancer cases are Expected results
diagnosed every year and over 1 million people die of cancer.The two
The project has the potential to accelerate development of advanced
leading cause of cancers in Europe are breast and prostate.Therefore devices, to ensure their dissemination, to increase the compromise
combating cancer is a major societal and economic issue for Europe. between treatment efficiency and patient safety, to consolidate
To face these new challenges strong mobilisation among the scientific collaboration between European teams and to spread new methods
and knowledge through workshops.
community and industrial manufacturers is needed.
A major expected result of the project is to decrease the number of
Todays approaches to treat cancer are the surgical removal of the deaths due to primary tumours without metastases.
tumour tissue, radiotherapy, chemotherapy, and emerging immuno-
therapy.Among them radiotherapy remains a major technique to treat
cancer. More than a half of all cancer patients are treated by radiation
Coordinator
Jean-Philippe Nicola
therapy thanks to the technical progress made with irradiation Commissariat lEnergie Atomique (CEA)
equipment in the last years. For external radiation therapy (RT), high- 31-33, rue de la Fdration
energy photon or electron beams are mainly produced by linear 75752 Paris France
E-mail: jean-philippe.nicolai@cea.fr
accelerators, for internal radiation therapy or brachytherapy, Project web-site: www.maestro-research.org
radioactive sources are put in the tumour with undeniable advantages Key words: quality assurance, clinical validation, IMRT, proton-
therapy, multimodality image registration, virtual
for the patient in given situations. simulation software, Monte Carlo dose calcula-
tion TPS, in vivo dosimeters, risk assessment,
Aim accurate patient positioning
The present project,MAESTRO,proposes innovative research to develop Partners

and validate in clinical conditions the advanced methods and equipment
Ion Beam Applications S.A, Belgium
needed in cancer treatment for new modalities in high conformal Technische Universiteit Delft,The Netherlands
external radiotherapy employing electrons,photons and protons beams. Istituto Nazionale Di Fisica Nucleare, Italy
Dosisoft S.A, France
The project aims at improving the conformation of the dose delivered
Instytut Fizyki Jadrowej Im. Henrika Niewodniczanskiego,
to the target (tumoural tissues) whatever its shape in order to spare the Polska Akademia Nauk, Poland
surrounding tissues.To do this new technologies in the field of patient Eldim S.A, France
positionning and organ tracking,advanced software for treatment planning Nuclear Research and Consultancy Group,The Netherlands
system,dose calculation and measurement,are to be developed,and linked Universita Degli Studi Di Firenze, Italy
to the emerging IMRT (Intensity-Modulated RadiationTherapy) technique. REM Radioterapia SRL, Italy
Istituto Superiore Di Sanita, Italy
Coventry University, United-Kingdom
Programme of activities NPL Management Limited, United-Kingdom
MAESTRO incorporates major research and technological Institut Gustave Roussy, France
Centre National de la Recharche Scientifique, France
development programmes involving clinics and manufacturers which Centre National Franois Baclesse, France
will be linked throughout. The project includes four work packages Universitaet Duisburg-Essen, Germany
on research and development activities and two work packages of University of East Anglia, United Kingdom
training and management activities: Universidad de Castilla, La Mancha - Spain
University Hospitals Coventry and Warwickshire NHS Trust,
United Kingdom
Acronym: MAESTRO Centrum Onkologii Oddzial W Krakowie, Poland
Project number: LSHC-CT-2004-503564 Institut National de la Recherche en Informatique et en
EC contribution: 7 000 000 Automatique, France
Instrument: Integrated Project Universitat de Barcelona, Spain
Duration: 60 months
Scanditronix Medical AB, Sweden

195
CANCER CCPRB
Cancer control using population-based

registries and biobanks
Summary Aim
CCPRB is a Network of Excellence project within the Sixth Provide the study base for uniquely large population-based
prospective studies on cancer.
Framework Programme of the European Union. It is aimed at
Define and implement a European Quality Standard for biobanking.
improved control of cancer by facilitating research linking biobanks
and cancer registries. The project involves a systematic quality Define and promote the implementation of integrity-proof methods
for biobank-based research involving well defined and secure third
assurance of European biobanks, as well as improved integrity
party code-keeping systems.
protection in the handling of sensitive information in connection with
Enable large-scale, population-based research on:
biobank-based research.The samples in the biobanks will be used in
a) evaluation of cancer treatment and role of molecular markers in
large-scale cancer research searching for genetic and infectious causes
treatment selection;
to cancer, in particular in the areas of breast and colorectal cancer
b) identification and evaluation of genetic markers associated with
and childhood leukaemias.
increased cancer risk using over-generation linkages;
c) exploration and evaluation of intrauterine exposures associated
Background with increased cancer risk using overgeneration linkages;
Longitudinal studies nested in biobanks enable more reliable and d) design of optimal strategies for cancer prevention and its evaluation.
efficient study designs, both for design and evaluation of cancer
treatment and cancer prevention as well as for exploring and Establish a Europe-wide network for spreading the awareness of
evaluating etiologic hypotheses. However, several prerequisites apply: possibilities and best practice quality standards for biobank-based
research.
There must exist very large-scale biobanks with several decades of
follow-up.
It must be possible to link biobanks with quality-assured population-
based cancer registries to enable population-representative studies The samples in
with minimal case ascertainment bias. the prospective
research
Important problems regarding overview, accessibility, quality control,
biobanks are
phenotypic characterisation, efficiency and avoiding risks for violation
aliquoted into
of personal integrity must be addressed.
color-coded tubes
(buffy coat, EDTA-
The participants plasma, heparin-
plasma and
The present network has linked large biobank projects with up to 30
so on).
years of follow-up and >60 000 prospectively occurring cancer cases
and cancer registries with >40 years of population-based registration.
There are 19 partners in the project from nine European countries,
including e.g.sevencancer registries,20 biobank projects and a number
of platforms for advanced technological analysis of biobank samples.
The freezer
facility of the
Medical Biobank
in
Ume

196
CANCER
Coordinator Prof. Garnett, Geoffrey

Imperial College of Science,Technology and Medicine
Prof. Dillner, Joakim
Dept. Infectious Disease Epidemiology
Lund University
Faculty of Medicine
Department of Medical Microbiology
St Marys Hospital
Malomo University Hospital
Entrance 78,
Dr Lehtinen, Matti
205 02 Malmo, Sweden
University of Tampere Public Health School and Medical
Phone: + 46 40 338126 School
Fax: + 46 40 337312 Tampere, Finland
E-mail: joakim.dillner@mikrobiol.mas.lu.se Prof. De Paoli, Paolo
Centro di Riferimento Oncologico
Partners Department of Laboratory Medicine
Prof. Hakulinen,Timo Laboratory of Microbiology
Finnish Cancer Registry Aviano, Italy
Helsinki, Finland Dr Houlston, Richard
Dr Thoresen, Steinar Section of Cancer Genetics
Kreftregisteret/The Cancer Registry of Norway Institute of Cancer Research
Oslo, Norway Sutton, Surrey, United Kingdom
Prof. de Villiers, Ethel-Michele Dr. Grzybowska, Ewa
Centre of Oncology
Deutsches Krebsforschungszentrum Angewandte
Tumorvirologie/Tumorvirus-Charakterisierung M. Sklodowska-Curie Memorial Institute
Heidelberg, Germany Branch Gliwice
Department of Tumour Biology
Prof. Lenner, Per
Cancer Genetics Laboratory
Ume Universitet Institutionen fr Strlningsvetenskaper
Gliwice, Poland
Onkologi, Ume, Sweden
Dr Marc Arbyn
Prof. Jellum, Egil
Scientific Institute of Public Health
The Norwegian Cancer Society Institute of Clinical
Unit of Epidemiology I.P.H.
Biochemistry
Brussels, Belgium
Oslo, Norway
Prof. Buntinx, Frank
Prof. Hemminki, Kari
Limburgse Kankerstichting Limburg Cancer Registry
Karolinska Institutet Department of BioSciences (LIKAR),
Huddinge, Sweden Hasselt, Belgium
Prof. gmundsdttir, Helga M. Prof. Lve, Arthur
Icelandic Cancer Society Molecular and Cell Biology Landspitali University Hospital Department of Medical
Research Laboratory Virology
Reykjavik, Iceland Landspitali University Hospital
Dr. Koskela, Pentti Reykjavik, Iceland
National Public Health Institute Hansson, Mats G.
Uppsala University Dept. of Public Health
Department of Microbiology
and Caring Sciences
Laboratory of Prenatal Serology
Uppsala, Sweden
(Finnish Maternity Cohort serum bank)
Oulu, Finland
Prof. Bartram, Claus R Acronym: CCPRB
University Hospital Heidelberg EC contribution: 6 050 000
Institute of Human Genetics Instrument: Network of Excellence
Duration: 60 months
Heidelberg, Germany Starting date: 01/06/2004

197
CANCER eTUMOUR
Web-accessible MR decision support system for brain

tumour diagnosis and prognosis, incorporating in vivo
and ex vivo genomic and metabolomic data
Summary
The lifespan of the European population is increasing and,
accordingly, diseases that become prevalent in old age,
such as brain tumours, will afflict a larger percentage of
this population. In addition, brain tumours are now one
of the leading causes of death from cancer: the first in
children under the age of 15 and the second from age
15 to 34.Brain tumours do not have a lifestyle-associated
etiology, and so prevention is not yet possible. Diagnosis
and treatment of brain tumours is based on clinical
symptoms, radiological appearance and often a
histopathological diagnosis of a biopsy.
The current gold standard classification of a brain tumour

by histopathological analysis of biopsy is an invasive
surgical procedure and incurs a risk of 1-2% morbidity, in
addition to healthcare costs and stress to the patients.
For tumours that evolve slowly in malignancy (e.g.pilocytic
astrocytoma in children) repeated biopsy may not be
advisable at all. On the other hand, diagnosis using
Magnetic Resonance Imaging (MRI) is non-invasive, but
only achieves 60-90% accuracy depending on tumour type
and grade.Likewise,treatment response of histological or
radiologically similar tumours can vary widely,particularly
for childhood tumours. Therefore, there is a need to
improve brain tumour classification, and to provide non-
invasive methods for brain tumour diagnosis and
prognosis, to aid the patient management and to have a
personalised treatment. Two molecular techniques are
available to address these needs. Magnetic Resonance
Spectroscopy (MRS) which can provide metabolic
information on tissue either in vivo (non-invasive) or ex
vivo (biopsy) and more recent DNA microarray analysis can determine be used for developing new bio-markers for a more precise diagnosis
tumour phenotype from gene expression profiles and genotype.The aim and for developing more selective and appropriated treatments. A
of eTUMOUR project is to coordinate European health care particular and important feature of eTUMOUR is the quality control and
professionals with a validated Decision Support System (DSS) for non- validation system enclosed in the project that ensures the quality and
invasive diagnosis of brain tumours, and the monitoring of tumour efficacy of the final products.This European consortium is unique and
progression, and response, for future new therapies.This DSS product we are not aware of any similar system being developed anywhere else
is based in an improved classification of brain tumours using molecular worldwide.
technologies such as Genomic and Metabolomic whose contributions
will provide new knowledge of brain cancer biochemistry which could

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CANCER
Coordinator
Prof. Celda, Bernardo
University of Valencia
Spain
E-mail: bernardo.celda@uv.es
Project web-site: http://www.uv.es/etumour,
http://www.etumour.net
Key words: DNA, micro-arrays, HR-MAS of biopsies,
DSS, GUI, Molecular Imaging
Partners
Universitat Autnoma de Barcelona, Spain
St Georges Hospital Medical School, London, United
Kingdom
University Medical Centre Nijmegen,The Netherlands
Stichting Katholieke Universiteit,The Netherlands
INSERM U594, France
INSERM U318, France
MICROART, S.L., Spain
Hospital San Joan de Deu, Spain.
Pharma Quality Europe, s.r.l. Italy
Hyperphar Group SpA. Italy
Katholieke Universiteit Leuven, Research &
Development, Belgium
Siemens AG, Medical Solutions, Germany
SCITO S.A., France
Universidad Politcnica de Valencia, Spain
Deutsche Krebsforschungszentrum Heidelberg, Germany
BRUKER BIOSPIN SA, France
Institute of Child Health, University of Birmingham,
United Kingdom
FLENI, Argentina
Medical University Lodz, Poland
Acronym: eTUMOUR
Duration: 60 months

199
CANCER TRANSBIG
Translating molecular knowledge into early breast

cancer management: building on the Breast
International Group (BIG) network for improved
treatment tailoring
Summary to develop and run a major clinical trial aimed at validating the
hypothesis that understanding the genetic make-up (signature) of a
The key to individualising treatment for cancer lies in finding a way to tumour can lead to better targeted treatment.
quickly translate the discoveries about human genetics made by
laboratory scientists in recent years into tools that physicians can use Problem
to help make decisions about the way they treat patients.This area of
Breast cancer is the most common cancer among women in
medicine that links basic laboratory study to the treatment of patients developed countries, with one out of eight to ten women developing
is called translational research. TRANSBIG has been created as a the disease in her lifetime.While incidence has steadily increased over
multidisciplinary network of excellence devoted specifically to this type the past decades, only recently has a slight decrease in deaths from
breast cancer been noted, and that only in a few countries.
of research in breast cancer.
Breast cancer is curable in about 70% of cases if diagnosed and treated
TRANSBIG is a research network of 39 world-class institutions in 21 early enough. But because of uncertainty over the best treatment in
countries. Each participating organisation brings with it expertise that individual cases, many women receive chemotherapy or hormonal
ranges from being specialised in cutting-edge biomedical technologies treatment after surgery based on the assumption that the risk is high
and cancer treatment programmes to lobbying governments on behalf that their breast cancer will recur. However, some women benefit
significantly from such treatment and others only very little or not at
of patient groups and supporting cancer societies. As a network,
all.The reason for this is because breast cancer is a disease that develops
TRANSBIG will be dedicated to high-level collaboration that will very differently in each woman. If individual tumours were better
contribute dramatically to advancing individualised treatment for breast understood, physicians would be better able to make decisions about
cancer patients. Among its many strengths is the fact that it is linked to which treatments are best for individual patients and which patients
an already existing network of groups around the world that conduct need no further treatment after surgery at all. Presently it is estimated
that about 12% to 20% of patients are over-treated,resulting in avoidable
clinical breast cancer research together the Breast International costs both to health services (financial) and patients (side-effects).
Group (BIG).BIGs 33 member organisations are active in 36 countries.
The central secretariat is located in Brussels, and will coordinate the
activities of both TRANSBIG and BIG. By linking the two networks and
Technical approach
by benefiting from a central coordinating body, the fragmentation Although TRANSBIG will ultimately develop many projects,it will start
with a clinical trial called MINDACT (Microarray for Node Negative
currently existing in the field will be reduced,and translational research
Disease may Avoid Chemotherapy). This trial will compare two
in Europe will be strengthened and accelerated. different ways of assessing the probability or risk that a womans breast
New technologies will only gain acceptance by physicians and patients cancer will come back. The traditional method is based on
international guidelines and looks at specific characteristics such as
after first being validated in large, independent clinical trials. Microarray the size of a patients tumour and whether the disease has spread to
technology has enabled scientists to determine the signature of individual the lymph glands (nodes).The new method uses microarrays as a way
tumours,but it must be proven that this information is more reliable than of analysing the genetic components of a tumour. Specifically,
existing methods for determining how to best treat individual patients. traditional methods of assessing risk will be compared to a 70 gene
tumour signature identified by a group of scientists at the Netherlands
Cancer Institute that appears to predict very accurately whether a
Aim particular womans breast cancer will come back. MINDACT will
involve 5000 women over a three-year period.
to develop ways of individualising breast cancer treatment, so that
treatment is tailored to the person receiving it. Other cutting-edge techniques and technologies will be used in the
project over time,and tumour and blood samples donated by patients
to integrate, strengthen and facilitate translational clinical breast
will create an invaluable resource for further research that will help
cancer research in Europe and internationally by linking it to an
us to better understand and treat breast cancer.
existing network for clinical breast cancer trials (BIG).

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CANCER
Expected results
The European Organization for the Research and
Impact of MINDACT Treatment of Cancer, Brussels, Belgium
The TRANSBIG partners believe that the results of MINDACT will show University of Glasgow, Glasgow, United Kingdom
that using the new technology to assess risk will result in fewer women Universitaet Wien,Vienna, Austria
being treated unnecessarily.This, in turn, will mean that fewer women Grupo Oncologico Cooperativo Chileno de Investigacion,
will suffer from the unpleasant side-effects of chemotherapy. Not only Santiago, Chile
will the overall quality of life of breast cancer patients be improved, but Bank of Cyprus Oncology Centre, Nicosia, Cyprus
the health care costs associated with such cancer treatment will be Univerzita Karlova v Praze, Prague, Czech Republic
reduced as well, thus providing a significant benefit to society. Finsen Centre - Rigshopitalet, Copenhagen, Denmark
Institut Gustave Roussy,Villejuif, France
As the first project in TRANSBIG, MINDACT will also establish
West German Study Group, Universitaetsklinikum
valuable resources for future research and establish links between
Dusseldorf, Dusseldorf, Germany
research and biotechnology enterprises in order to develop further
Klinikum der Johann Wolfgang von Goethe Universitaet,
diagnostic tools that can be widely disseminated and easily used by
Frankfurt, Germany
scientists and physicians alike.
Technische Universitaet Muenchen, Munich, Germany
Impact of TRANSBIG Universitaetsklinikum Eppendorf, Hamburg, Germany
The long-term aim is to develop TRANSBIG into a permanent National and Kapodistrian University of Athens, Athens,
network for translational research that is complementary to the Greece
clinical work done by BIG.This guarantees a connection between what St Vincents University Hospital, Dublin, Ireland
scientists learn in the laboratory and what physicians and patients Gruppo Oncologico Italiano di Ricerca Clinica, Parma, Italy
decide together about treatments in the clinic. Centre Hospitalier de Luxembourg, Luxembourg
Universiteit Maastricht, Maastricht,The Netherlands
But TRANSBIGs reach will be wider than simply research. It will also
Medical University of Gdansk, Gdansk, Poland
be concerned with education through the provision of traineeships
Portuguese Institute of Oncology Francisco Gentil, Porto,
for young scientists and physicians and public education on the issues
Portugal
involved with genomics by working closely together with cancer
societies and patient advocacy groups. N. N. Blokhin Cancer Research Centre, Moscow, Russia
Institute of Oncology, Ljubljana, Slovenia
By bringing together scientists, clinicians, and representatives from Institute of Oncology of Southern Switzerland Mendrisio,
patient groups, cancer societies and industry,TRANSBIG will bring a Switzerland
coherence and synergy to breast cancer research that has previously Marmara University Medical School Hospital, Istanbul,
not existed in Europe. Turkey
Federation of European Cancer Societies, Brussels, Belgium
Europa Donna The European Breast Cancer Coalition,
Milan, Italy
Coordinator Instituto de Patologia e Imunologia Molecular da
Piccart, Martine Universidade do Porto, Porto, Portugal
Jules Bordet Institute GSF Forschungszentrum fuer Umwelt und Gesundheit,
1, rue Hger-Bordet Munich, Germany
1000 Brussels, Belgium Agendia,Amsterdam,The Netherlands
Phone: + 32 2 541 3526 International Institute for Drug Development, Brussels,
Fax: + 32 2 541 3199 Belgium
E-mail: transbig@bordet.be Fundacion Institut per la Recerca Vall dHebron, Barcelona,
Key words: Breast cancer Spain
Grupo Espaol de Estudio,Tratamiento y otras Estrategias
Partners Expirementales en Tumores Slidos, Madrid, Spain
Breast International Group (BIG-aisbl), Brussels, Belgium Swiss Institute of Bioinformatics, Lausanne, Switzerland
Institut Jules Bordet / Jules Bordet Instituut, Brussels, University of Oxford, Oxford, United Kingdom
Belgium
The Netherlands Cancer Institute, Amsterdam,
The Netherlands Acronym: TRANSBIG
Istituto Europeo di Oncologia - European Institute Project number: LSHC-CT-2004-503426
of Oncology, Italy EC contribution: 7 000 000
Karolinska Institutet, Stockholm, Sweden Duration: 60 months
University of Wales, Swansea, United Kingdom Starting date: 01/03/2004

201
CANCER European LeukaemiaNet
Strengthen and develop scientific and technological excellence

in research and therapy of leukaemia (CML,AML,ALL, CLL, MDS,
CMPD) by integration of the leading national leukaemia networks
and their interdisciplinary partner groups in Europe
Summary guidelines), industry and SMEs across Europe to form a cooperative
network for advancements in leukaemia-related research and health
Leukaemias are a challenge to society and a cost factor because of their care. Integration will be supported by central information,
communication, education and management structures. Other goals
frequency in all age groups.They also serve as a model for a variety of
are to intensify target and drug discovery, to shorten the time
diseases and possess exemplary relevance for basic research and patient period to clinical translation, to apply advanced genomics, telematics
care. Leukaemia research and therapy have achieved high standards and and biotechnology to therapeutic progress and to promote
research relevant also for solid cancers by large clinical trials.
even a leading position in several European countries with regard to
Furthermore, meta-analyses of specific subaspects, elaboration of
clinical trials,standardisation of diagnostics and molecular studies of signal prognostic scores, recognition of gender-specific differences,
transduction and gene expression. A true European world leadership, creation of uniform data sets for trials and registration, introduction
however, has not been accomplished yet due to national fragmentation of standards for diagnostics and treatment and development of
evidence-based guidelines will be promoted throughout Europe.The
of leukaemia trial groups,diagnostic approaches and treatment research proposed network will have the expertise and critical mass for
activities and a need for central information and communication European added value and world leadership. It will structure
structures. European research durably, spread European scientific excellence
in the field of leukaemias and can start immediately.
The 78 leukaemia trial groups and their 83 interdisciplinary partner
Aim groups representing several thousand participating centres and ten
Multiple drug resistant bacteria are a major threat to human health thousands of study patients treated within the trial groups form
and a significant burden on already stretched medical budgets.This the backbone of the network. The network consists of 18 work
threat is predicted to increase in severity, and remedial actions of packages. Of these, six deal with the various diseases (AML, ALL,
reducing antibiotic use in animal husbandry and limiting current CLL, CML, MDS, CMPD) and represent sub-networks on their own.
prescribing activities for non-lethal human disease are both unlikely Nine work packages represent interdisciplinary platforms which
to reduce the danger in the short-term. Of major concern are provide the support and research expertise required for high quality
antibiotic-resistant nosocomial infections.The economic and societal networking and excellence. Three core work packages provide
costs of these hospital-acquired infections are enormous: the UK central communication and management services for the whole
National Health Service has estimated an annual cost of 1.5 billion network.
for extra patient care and that 5000 deaths result each year. In
The integration and interdisciplinary cooperation brings together 116
addition, the incidence of infection by multiple drug resistant strains
participants and approximately 900 researchers from 22 countries.
of Mycobacterium tuberculosis, the causative agent of the tuberculosis,
The network will overcome national fragmentation and provide the
is rapidly increasing, particularly among the disadvantaged in society.
critical mass to achieve research and treatment goals that cannot be
Investment in R&D into antibiotic discovery by the major
achieved by single European countries.
pharmaceutical companies has declined dramatically in the last 15
years as a perception has taken hold that easily obtained natural
products may have been fully exploited. Hence conventional Expected results
screening of natural products for new drugs is no longer considered
economically worthwhile. Unfortunately, the downturn in drug 1. Establishment of central information and communication structures to
discovery has coincided with a dramatic worldwide increase in the create networks and platforms for all leukaemias and their interdisciplinary
incidence of resistance to all the antibiotics currently used in partners.
medicine. Integration is mediated by exchange of current trial protocols and
The objective is to integrate the 78 leading leukaemia trial groups procedures, information on participating centres and recruited
(chronic myeloid leukaemia (CML), acute myeloid leukaemia (AML), patients and employment of uniform common data sets for
acute lymphoblastic leukaemia (ALL), chronic lymphoid leukaemia comparable study outcomes and evaluations provided by the
(CLL), myelodysplastic syndromes (MDS), chronic biometrical center (WP 17).This objective will be achieved through
myeloproliferative disorders (CMPD)), their 83 interdisciplinary central services: Network Management Center (NMC, WP 1),
partner groups (diagnostics, treatment research, registry, European Leukaemia Information Center (ELIC,WP 2) and Central

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CANCER
Information and Communication Services (CICS,WP 3).The central roles, prevention of lung collapse during respiration and provision
service groups benefit from a three years' experience in similar of a first line of defence against the extremely varied range of
tasks for the German Competence Network for Acute and Chronic particles, allergens and microbes that are present in the
Leukaemias funded by the German Ministry for Education and environment. The lung surfactant is a surface-active mixture of
Research (BMBF) and provide the basis for a head start of the phospholipids and four main surfactant proteins SP-A, SP-B, SP-C
network. These groups will also provide training programmes, and SP-D.The SP-B and SP-C proteins are small, highly hydrophobic,
workshops, symposia, exchange of researchers and information polypeptides, which are strongly associated with the phospholipid
programmes, thereby spreading excellence to health care portion of the surfactant, whereas SP-A and SP-D are large
personnel, researchers and to other countries not yet participating (approximately 600kDa) and complex, disulphide-bonded, proteins
in the network.With the support of NMC (WP 1) the network will of a more hydrophilic nature.They can bind, via their lectin domains,
be managed in a two-layer networking organisation. Clinical trial to arrays of carbohydrate structures on the surfaces of pathogenic
groups for each leukaemia and their interdisciplinary partner will microbes and to glycosylated allergens, thus initiating defence against
form their own European subnet organizations with coordinators, a range of viral, fungal and bacterial lung infections and modulating
steering groups and management structures. These subnets and allergic reactions.There is evidence of lowered levels of SP-A, and
platforms will then be integrated in the European Leukaemia SP-D, in the lung surfactant of a growing number of types of infection-
Network which will conduct the integrated research programme or allergy-mediated lung inflammation, which strengthens the case
detailed below. The network will be managed by the Network for testing the use of recombinant forms of these proteins as
Coordinator (NC), the Scientific Network Manager (SNM) and the therapeutic alternatives to antibiotics.
Steering Committee (SC) consisting of the coordinators (=Lead
5. European Registry (all leukaemias).
participants) of the work packages (WP). The University of
Heidelberg will provide the expertise for financial, legal and A European registry will allow to determine incidence and disease
contractual management. patterns across Europe including gender, age and ethnic differences,
investigate familiar aggregations, overlap syndromes or precursor
2. Set-up of European networks for each leukaemia and related syndrome.
conditions, explore risk factors associations and differences in gene
These networks will comprise the national trial groups for each environment interaction, using data from cytogenetic analyses (WP
leukaemia and represent the first stage of networking and European 11) and genomic profiling (WP 13),perform quality of life assessments,
integration. recognize sub-entities on the basis of cytogenetic or gene profiling
information, follow-up patients for the development of prognostic
3. Set-up of European platforms for each interdisciplinary specialty.
These platforms are sub-networks of excellence
of diagnostic, therapeutic and biometric research
groups on their own and constitute inter-
disciplinary partners enabling the clinical trial
groups to achieve the high quality patient care and
research required for European leadership.
4. Performance of clinical trials (all leukaemias).
Employing uniform common data sets the trial
groups will continue their current trials funded by
alternative sources and will start new trials using
diagnostic standards established by the diagnostic
platforms (WPs 10-13) and employing new drugs
provided by pharmaceutical companies and/or the
sub-network on treatment research/new targets/
new drugs (WP 16). Criteria for accreditation of
trials will be set up.
Lung infection and inflammation is a growing
problem within all states of the EU, and the
infections are routinely treated with antibiotics.
The pharmaceutical industry is interested in the
development of protein therapeutics, which can
be used as alternatives to antibiotics.There is a
relatively fragile protective barrier, the alveolar
Geographic distribution of lead participants and participants representing national study
lining layer, which controls the interaction
groups comprising more than 1,000 centers in 22 countries
between the atmosphere and the lung.The film,
known as lung surfactant, plays two important

203
CANCER
scores for old and new therapies and determine proportions of 7. Metaanalyses and guidelines
patients in individual countries treated on specific protocols or with
Whenever randomised trials are available for analysis (mostly CML
specific therapies e.g. SCT (WP 14).The registry will be run by the
and AML), meta-analyses will be performed and published (WP 17).
expert group Biometry for Registry, Epidemiology, Metaanalyses and
On the basis of meta-analyses,evidence-based guidelines (WP 18) will
Prognosis (WP 17). This group has gained a long-standing broad
be worked out and used for the improvement of patient management
experience in collecting data, performing meta-analyses and
and for educational purposes (training programmes, workshops in
establishing prognostic scores. The database established by the
associated countries, exchange of researchers and physicians for
network will have far-reaching implications for research and public
training purposes).Meta-analyses will be also performed on combined
health planning far beyond the period of EC funding.
data sets with rare subtypes of leukaemias (WP6).
6. Standardisation
Standardised and quality controlled diagnostic
procedures and therapies constitute the basis for
improvements of clinical outcomes. This
concerns all diagnostic approaches such as
morphological diagnosis of blood and marrow
cells (WP 10), cytogenetics (WP 11), detection
of minimal residual disease (WP 12) and gene
expression profiling (WP 13) as well as therapies
such as transplantation,anti-infection prophylaxis
and treatment and the testing of new drugs in
phase I/II trials (WP 14-16).The establishment
of standards for a wide spectrum of diagnostic
and therapeutic applications will raise the quality
of research and patient care beyond the period
of EC funding and will predictively have a
profound impact on outcome as measured by
prolongation of life and cure rates across Europe.
Network Structure: The different platforms are grouped into workpackages

(WP). Central services: WP 1: Network Management Center (NMC),WP2:
Leukemia Information Center (ELIC),WP3: Central Information and
Communication Services (CICS). Clinical trial platforms:WP4: CML,WP5:
AML,WP6: ALL,WP7: CLL,WP8: MDS;WP9: CMPD. Diagnosis/Follow-up:
WP10: Diagnostics;WP11: Cytogenetics;WP12: MRD;WP13: Gene Profiling.
Treatment Research:WP14: Stemcell Transplantation;WP15: Supportive Care,
Anti-infection Prophylaxis and Treatment;WP16:Treatment Research / Drug
Development. Registry/Education:WP 17: Biometry of Registry, Epidemiology,
Metaanalyses and Prognosis;WP18: Guidelines.

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CANCER
Coordinator Universitt Kln, Germany

Prof. Hehlmann, Rdiger Stichting Katholieke Universiteit, Univ. Medical Center
Nijmegen,The Netherlands
III. Medizinische Universittsklinik
Azienda Ospedaliera - Ospedali Riuniti di Bergamo, Italy
Ruprecht-Karls-Universitt Heidelberg
IRCCS Policlinico S. Matteo, Italy
Wiesbadener Str. 7-11
Universit Henri Poincar Nancy 1, France
68305 Mannheim, Germany
St. Marien-Krankenhaus Siegen gem. GmbH, Germany
Phone: + 49 621 383 4115
Medizinische Unversitt Wien, Austria
Fax: + 49 621 383 4201
Philipps-Universitt Marburg, Germany
E-mail: R.Hehlmann@urz.uni-heidelberg.de
King's College London, United Kingdom
Project web-site: http://www.leukaemia-net.org
Imperial College London, United Kingdom
Key words: leukaemia, CML, AML, ALL, CLL, MDS,
CMPD University of Basel, University Hospitals - Switzerland
Universitt Leipzig , Germany
Partners
Karolinska Institutet, Sweden
Universittsklinikum Frankfurt, Germany
Eberhard-Karls Universitt Tbingen, Germany
Ludwig-Maximilians-Universitt Mnchen, Germany
Uniersity of Newcastle upon Tyne, United Kingdom
Uppsala Universitet, Sweden
Association pour la Recherche sur les Transplantations
Universita di Bologna - Unita Complessa di Istituti di Medullaires, France
Cardiologia ed Ematologia, Italy
Universit de Poitiers, France
Ruprecht-Karls-Universitt Heidelberg, Germany Acronym: European LeukaemiaNet
Project number: LSHC-CT-2004 503216
Universittsklinikum Mnster, Germany EC contribution: 6 000 000
University of Wales, College of Medicine, United Duration: 60 months
Kingdom
Fundacion Hospital Universitario La Fe, Spain
Les Hospices - CHUV - Switzerland
Dipartimento di Biotecnologie Cellulari ed Ematologia,
Universita degli Studi di Roma La Sapienza, Italy
Leiden University Medical Center,The Netherlands
Institut Pasteur, France
Universitt Ulm, Germany

205
CANCER DNA METHYLATION
Epigenetic profiling of breast cancer: prognostic

and therapeutic applications
Summary
A key clinical question in the management of
primary breast cancer concerns the
assessment of information provided by risk
factors measured in blood and tissue that
support the choice of an optimal adjuvant
treatment regimen for the individual patient.
The basic understanding of breast cancer
initiation and progression is still far from being
understood. Apart from that, we will need to
develop highly reliable methods to classify
breast cancer patients in different risk groups,
based on their detailed tumour characteristics.
Cancer is a genetic as well an epigenetic
disease. A prominent epigenetic alteration is
DNA-methylation in the promoter region of
the gene that prevents the gene to be
expressed.Our translational project uses newly
developed state-of-the-art DNA methylation
approaches that recently have become available
through partners of this consortium.The aim The fifth base in the genome:
of the project is to develop prognostic and Methylation of the carbon 5 position is the epigenetic modification in the mammalian
predictive DNA methylation profiles for breast genome that contributes to cancer Epigenomics AG, Berlin.
cancer patients.
is due to imperfect technologies, limited size and heterogeneity of
Problem patient cohorts studied and lack of reproducibility and uniform assay
methodologies as well as quality assurance programs.
Breast cancer is the leading malignancy in women and a leading cause
of death.The mortality rate has slightly decreased over the past few
years, but statistic tends indicate that the incidence is rising further Background on DNA
due the aging of the population.The high importance of the necessity methylation in cancer
of improved breast cancer diagnosis and therapy is without any doubt.
Markers that allow better targeting of available therapies to particular DNA methylation occurs only on cytosines, and methyl-cytosine is
patients will most likely improve outcome in cancer in the future. considered the fifth base (Figure 1).In cancer,DNA methylation shifts
Indeed, the dilemma of optimal treatment of primary breast cancer towards the regulatory regions of genes resulting in silencing of
is complex for both patients with primary breast cancer and for tumour suppressor genes. Promoter DNA methylation is a booming
patients with recurrent disease (metastases). To enable and allow field in cancer biology since it has become apparent that this
tailored therapy concepts that take the individual tumour biology into epigenetic type of gene regulation contributes to many aspects of
account, new and specific tumour-associated factors are needed that cancer biology, such as tumour initiation, tumour aggressiveness,
guide the physician in the prediction of the patient's prognosis and of tumour metastasis, and tumour behaviour during systemic therapy.
therapy response. Even though enormous efforts have been put into
the identification of prognostic and predictive factors over the years
the successful identification of strong markers has been limited.This

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DNA methylation
as diagnostics
Several properties make
epigenetic changes at the level of
the DNA attractive as diagnostic
targets. DNA methylation is very
stable and localised; it can be
turned into genetic information
and subsequently amplified by
classic PCR. Finally, methylation
detection is feasible in fixed,
paraffin-embedded material.These
features allow for sensitive and
quantitative detection and rapid
transfer of a diagnostic test to DNA methylation as molecular switch:
clinical routine. Furthermore, Methylation of cytosine in the regulatory region of a gene turns it ON or OFF.This way it con-
since DNA methylation regulates tributes to the cancer phenotype with respect to aggressiveness and therapy responsiveness.The
gene expression and results from project aims to identify the key molecular switches. Since the simple nature of the change, methy-
a simple change, a methylation on lation or not, it can be treated as binary information Epigenomics AG, Berlin.
a cytosine residue or not, it can be
considered as a binary genotypic
change that is responsible for the
observed phenotypic difference (Figure 2). Although DNA- other types of systemic therapy.To identify the markers genome-wide
methylation markers have not found their way to the clinic yet, high-throughput DNA methylation screening will be performed on
they could be important and powerful diagnostic or predictive well-defined breast tumour tissue banks (>20,000 tumour tissue
markers not far ahead. samples) with complete computerized follow-up information on
patient's course of the disease and treatment response.We intend to
identify DNA methylation markers that predict prognosis and therapy
Aim success. The 9 participating centres contribute complementary
The key activity of this project is to identify and validate DNA proprietary technical expertise, large and well-documented tissue
methylation markers with clinical value. The project addresses the resources, and extensive clinical knowledge.To maximize the chances
clinical need to come to tailored treatment of breast cancer patients, to successfully identify specific risk-associated targets for tumour
of whom a large proportion is over-treated, or would benefit from aggressiveness and effectiveness of systemic endocrine and
chemotherapy,DNA is prepared from carefully selected tumours from
Binary epigenetic predictor:

Predictive DNA methylation
patterns identified during this
project and indicated by the bar-
code here can guide the clinician to
decide whether to treat or not the
treat and to determine the best
type of treatment for the individual
patient Epigenomics AG, Berlin.

207
CANCER
the large tissue collectives that are available through members of this
consortium.After the identification of potential target genes for some Prof. Dr. Nils Brnner
of the major clinical questions regarding breast cancer prognosis and
therapy prediction, validation steps are carried out. The latter also Royal Danish Veterinary and Agriculture University
involves biochemical validation of mRNA and protein expression of Institute of Pharmacology and Pathobiology
the differentially methylated genes, and clinical validation of the newly
discovered targets in large numbers of tumours. Frederiksberg C, Denmark
The ultimate goal of the project is to improve breast cancer prognosis Dr. Fred CGJ Sweep
and treatment in the European Community and beyond and give the Department of Chemical Endocrinology
European Union the lead in this important field of cancer diagnostics.
University Medical Center Nijmegen
Expected results
and potential applications Dr. Sabine Maier
Epigenomics AG
The prime spin-off of our current project is to provide a major
refinement of breast cancer classification allowing accurate Berlin, Germany
prediction of patient prognosis and response to therapy based on
Dr. Frdrique Spyratos
newly identified DNA methylation markers as exemplified in Figure
3. The intellectual property generated during this project will be Centre Ren Huguenin
patented. We expect the diagnostic tests to be used for clinical
Laboratoire d'Oncobiologie
decisions about the choices of treatment.
St-Cloud, France
Dr.Tanja Cufer
Coordinator Department of Medical Oncology
Dr. John A. Foekens
Institute of Oncology
Department of Medical Oncology
Ljubljana, Slovenia
Erasmus MC Rotterdam
Dr. Joe Duffy
Josephine Nefkens Institute, Rm BE426
National University of Ireland
Dr. Molewaterplein 50
Nuclear Medicine Department
3015 GE Rotterdam,The Netherlands
St.Vincent's University Hospital
Phone: +31 10 4088369
Dublin, Ireland
Fax: +31 10 4088365
Dr. Serenella Eppenberger-Castori
E-mail: j.foekens@erasmusmc.nl
Prof. Dr. Urs Eppenberger
Project web-site:
Stiftung Tumourbank Basel
http://www.erasmusmc.nl/interne_oncologie/FP6/
Riehen, Switzerland
Key words: breast cancer, DNA methylation, diagnostic
markers, prognosis, chemotherapy, endocrine therapy.
Partners Acronym: DNA METHYLATION

Prof. Dr. Manfred Schmitt Instrument: Specific Targeted Research Project
Dr. Nadia Harbeck Duration: 36 months
Department of Obstetrics and Gynecology
Technische Universitt Mnchen
Klinikum rechts der Isar
Munich, Germany

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European MCL Network CANCER
European Mantle Cell Lymphoma Network:Translation evalua-

tion of molecular prognostic factors and pharmacogenomics in
European interdisciplinary collaboration
Mantle cell lymphoma (MCL) is a subtype of malignant lymphoma with 1. Prospective evaluation of combined immunochemotherapy and
myeloablative consolidation in patients <65 years: R-CHOP
an especially poor prognosis. Recently, a European MCL Network of followed by myeloablative consolidation vs. R-CHOP/R-DHAP
clinicians, basic scientists and pathologists has been established to followed by high dose Ara-C therapy
investigate the clinical as well as molecular aspects of MCL. In previous 2. Prospective evaluation of combined immunochemotherapy and
clinical trials,the superiority of innovative treatment options (high dose different maintenance strategies in patients >65 years: R-CHOP vs.
therapy,combined immuno-chemotherapy) has been confirmed,and cell R-FC followed by IFN vs. Rituximab maintenance;
proliferation has been identified as the most important prognostic 3. Regular histomorphological panel review of study cases (subtyping
according to cytological criteria);
factor. Based on these extensive prerequisites, we have initiated a
translational approach to evaluate innovative treatment options (like 4. Prospective evaluation of a panel of proliferation-associated and
new oncogenic markers (immuno-histochemistry);
immuno-chemotherapy, radioimmunotherapy, high dose consolidation
and molecularly targeted approaches) and molecular prognostic 5. Prospective evaluation of MRD detection (PCR, FACS, FISH) in the
patient cohort of the European MCL Network;
markers in prospective randomised studies.All study cases are subjects
6. Prospective evaluation of the proliferation-associated gene
of innovative molecular analyses and continuous detection of minimal
signature in the patient cohort of the European MCL Network
residual disease.This translational approach will not only lead to more (RNA array).
effective therapeutic strategies based on the molecular profiling but also
pave the way to molecular targeted treatments.
Problem
Mantle cell lymphoma (MCL) is a distinct, clinically very aggressive
subentity of malignant lymphoma with a median survival of three years.
However, a small subset of patients represents long-term survivors.
So far, the discriminative power of different prognostic parameters
has been limited and did not allow the reliable identification of the
individual patient's risk profile. Thus, a better understanding of the
underlying molecular mechanisms is eagerly warranted.
Aim
Based on the previously established European MCL Network of
clinicians, basic scientists and pathologists and the recent development
of innovative molecular techniques (matrix CGH,RNA array chips,RQ-
PCR, proteomics), we are performing a global approach to investigate
innovative treatment options of MCL and evaluate new predictive
(pharmacogenomics, minimal residual disease) and prognostic
molecular markers (genomic alterations, RNA/proteome profiles) in
controlled prospective studies. This translational approach of the
European MCL Network will not only lead to more individualised
therapeutic strategies based on the molecular risk profile but will also
finally elucidate the way to future molecular targeted treatment options
in a subtype of malignant lymphoma with an otherwise dismal clinical
outcome.

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CANCER
Coordinator
Malignant lymphoma is currently the fourth most frequent malignant
disease and displays the highest increase in annual incidence of all Dr Dreyling, Martin
hematological neoplasias. In this regard, the exploration of innovative Wolfgang Hiddemann University Hospital Grohadern
treatment strategies and evaluation of prognostic markers in the
rather rare disease of mantle cell lymphoma is also a model disease Ludwig-Maximilian-University Munich
for much more frequent diseases which have a profound impact on Dept. of Medicine III
the public health system as well as the general society.The prospective
studies of the European MCL Network studies will enable us to gain Marchioninistr. 15
a deeper understanding of the pathophysiological network of cell 81377 Mnchen, Germany
programme regulation in malignant lymphoma. In addition, applying
this multivariate procedure, the critical biological players of malignant Phone: + 49 89 7095 2202
transformation will be identified which may represent the suitable Fax: +49 89 7095 2201
target genes of future treatment strategies in a disease with otherwise
dismal prognosis. Moreover, this collaboration of outstanding clinical E-mail: martin.dreyling@med.uni-muenchen.de
as well as molecular scientists will be a paradigm for other fields of Project web-site: www.lymphome.de
biological research interlinking clinical and basic science as well as
scientific excellence from all over Europe. Key words: mantle cell lymphoma, therapy, molecular
risk factors, minimal residual disease (MRD),
pharmacogenomics, RNA array profiling,
proteomics
Partners
Dr Smedegaard, Niels
Andersen Rigshospitalet
University Hospital Copenhagen
Dept. of Hematology
Copenhagen, Denmark
Prof. Campo, Elias
Hospital Clinic
University of Barcelona
Hematopathology Section
Laboratory of Pathology
Barcelona, Spain
Prof. van Dongen, J J M
Erasmus University Medical Center Rotterdam
Department of Immunology
Rotterdam,The Netherlands
Prof. Kluin, Philip M
Academic Hospital Groningen
Dept. of Pathology and Laboratory Medicine

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CANCER
Prof. van Krieken, Johannes H J M Prof. Salles, Gilles

Stichting Katholieke Universiteit Universite Claude Bernard Lyon-1
University Medical Centre Nijmegen Centre Hospitalier Lyon-Sud
Department of Pathology Service dHematologie
Nijmegen,The Netherlands Pierre-Benite, France
Prof. Macintyre, Elizabeth Prof. Schlegelberger, Brigitte
Assistance Publique-Hopitaux de Paris Medizinische Hochschule Hannover
Hopital Necker-Enfants Malades Inst. fr Zell- und Molekularpathologie
Hematology Laboratory Hanover, Germany
Paris, France Dr Siebert, Reiner
Dr Martinez-Climent, Jose Angel University Hospital Schleswig-Holstein
Fundacion Para la Investigacion Medica Aplicada (FIMA) Campus Kiel
Centro para la Investigacion Medica Aplicada (CIMA) Institute of Human Genetics
Laboratorio de Oncologia Molecular 108 Kiel, Germany
Universidad de Navarra Dr Stilgenbauer, Stephan
Pamplona, Spain Universittsklinikum Ulm Innere Medizin III
Prof. Meitinger,Thomas Ulm, Germany
GSF National Research Institute for Environment and Dr Thieblemont, Catherine / Dr Callet-Bauchu,
Health Evelyne
Institut fr Humangenetik Ingolstdter Universite Claude Bernard Lyon-1
Neuherberg, Germany Equipe Associee Pathologie des Cellules Lymphoides
Dr Ott, German / Dr Rosenwald, Andreas Pierre-Benite, France
Bayerische Julius-Maximilian-Universitt Wrzburg Dr Trnny, Marek
Pathologisches Institut Univerzita Karlova v Praze (Charles University of Prague)
Wrzburg, Germany 1st Dept. of Medicine
Prof. Parwaresch, Reza / Dr Klapper,Wolfram 1st Faculty of Medicine
Universittsklinik Kiel Institut fr Hmatopathologie Praha, Czech Republic
Wrzburg, Germany Dr Walewski, Jan
Dr Pott, Christiane Maria Sklodowska-Curie Memorial Cancer Center
University Hospital Schleswig-Holstein Institute of Oncology
Campus Kiel Warszawa, Poland
II. Med. Klinik und Poliklinik
Kiel, Germany
Acronym: European MCL Network
Dr Ribrag,Vincent Project number: LSHC-CT-2004-503351
Institut Gustave Roussy, Sce d'Hematologie Instrument: Scientific Targeted Research Project
Duration: 36 months
Villejuif, France Starting date: 01/07/2004

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CANCER BRECOSM
Identification of molecular pathways that regulate

the organ-specific metastasis of breast cancer
Summary Mammary tumor
showing the lymphatic
The objectives of this project are to identify genes, proteins and vessels that impinge
molecular pathways involved in regulating the metastasis of breast cancer upon the tumor (blue
to specific organs.To achieve these objectives we will use a combination staining). Increased
lymphatic vessel densi-
of gene expression profiling, bioinformatic analysis, histology of human
ty promotes metastasis
female breast cancer samples, genetic manipulation of transplantable to regional lymph
tumor cells and transgenic mouse technology.In addition to finding new nodes
genes, we aim to analyse to what extent genes already known to play a
role in breast cancer metastasis specify which organs breast tumors improved clinical decision-making, prognostic evaluation and therapy in
metastasise to.We will also establish how the currently known genes breast cancer.
that are associated with breast cancer dissemination and the new ones Aims
we identify fit together into pathways that regulate organ-specific
to identify genes that are specifically up- or down-regulated in breast
metastasis.These findings will be coupled with the analysis of clinical trials cancer metastases in specific organs;
in which participants in this consortium are involved.Further deliverables
to identify gene expression signatures in primary breast tumours
include the development of improved animal models for the study of that predict metastasis to specific organs or predict the prognosis
breast cancer metastasis, and the development of diagnostic methods of ductal carcinoma in situ (DCIS);
for determining whether primary tumours already have metastatic to determine whether genes already associated with breast cancer
potential. Together, the work packages in this project will establish a invasiveness and metastasis are expressed in metastases in all or only
a subset of organs;
pipeline of activities that unite basic research into the organ-specific
to demonstrate whether genes found to be specifically expressed
metastasis of breast cancer with target validation and clinical application.
in breast cancer metastases to given organs play a functional role in
organ-specific metastasis;
Problem to elucidate molecular pathways that regulate breast cancer
Breast cancer is a major health issue and is highly gender relevant. It is metastasis to specific organs;
the most often diagnosed female cancer, and the majority of cases are to develop improved animal models for studying organ-specific
already invasive at diagnosis.More than 17% of cancer deaths result from metastasis of breast cancer;
breast tumours, making breast cancer a major societal problem.
to produce a prototype microarray chip for diagnostic/prognostic
Treatment involves radical and disfiguring surgery, often with long-term
evaluation;
side effects such as the development of lymphedema of the arm, and
radiotherapy and chemotherapy,again associated with severe side effects. to apply the findings on organ-specific metastasis in the clinical
The effects of metastatic spread of the tumour cells and the formation setting.
of secondary deposits in a wide variety of organs are the cause of death
due to breast cancer. Metastases to organs such as bone and brain are
major causes of suffering in terminally ill patients.
Expected results
The incidence of breast cancer increases sharply between the ages The results of this project will begin to explain the molecular basis
of 30 and 50 meaning that many women in the prime of life are affected for organ-specific metastasis in breast cancer.
by this disease. Not only does this mean that many families are This project will identify regulatory pathways and cellular events that
traumatised, but it also has severe economic consequences, removing coordinate organ-specific metastasis of breast cancers.Novel targets
economically active women from society. Further economic for therapy will thereby be identified.
consequences arise as a result of the high health care costs associated This project will identify gene expression signatures in tumours
with treating breast cancer patients. associated with metastasis to particular organs. This will be an
Clearly improvements in the treatment and management of breast important advance in understanding the underlying genetic changes
cancer would have impact on both health and the economy.By analysing that regulate organ-specific metastasis in breast cancer.
molecular mechanisms that regulate organ-specific metastasis in breast This project will bring together European experts working on
cancer, the BRECOSM project will identify tools that will contribute to different aspects of the molecular basis of tumour metastasis.As a

212
CANCER
result of coordinated efforts, pathways that regulate metastasis to

specific organs will be determined, and genes that play a functional
role in organ-specific metastasis will be identified. Coordinator
This project will generate improved animal models for the further Sleeman, Jonathan
study of breast cancer metastasis to specific organs. Forschungszentrum Karlsruhe
Institut fr Toxikologie und Genetik
This project will identify gene expression signatures in primary
breast tumours that predict patterns of metastasis.The application Postfach 3640
of these findings will assist clinical decision making and prognostic 76021 Karlsruhe, Germany
evaluation. Phone: + 49 7247 826089
E-mail: sleeman@itg.fzk.de
Potential applications Project web-site:
http://itgmv1.fzk.de/itg/brecosm/brecosm.htm
The gene expression signatures in primary tumours identified in this
Key words: cancer, breast, metastasis, gene
project that predict organ-specific metastasis and the prognosis of DCIS
expression profiling
will have obvious potential for clinical application in diagnosis and
prognostic assessment.Gene expression signatures in primary tumours
associated with either organ-specific metastasis or progression of DCIS
Partners
will be extensively validated retrospectively and as a prelude to Van Roy, Frans
introducing these gene expression signatures into clinical diagnosis and Department for Molecular Biomedical Research (DMBR)
prognostic evaluation, we will perform prospective studies to VIB - Ghent University,
demonstrate the efficacy of examining gene expression signatures in
Ghent, Belgium
primary breast cancers for predicting the likelihood and location of
metastases and the probability that DCIS will progress and metastasise Christofori, Gerhard
after partial mastectomy. The prototype microarray chips we create Institute of Biochemistry and Genetics, Department of Clinical-
based on gene expression profiles produced as part of this project will Biological Sciences, University of Basel
be applied in the clinical setting to investigate their diagnostic and Basel, Switzerland
prognostic value for breast cancer in a prospective study. This will Lukanidin, Eugene
constitute a major step towards exploitation of the results.It is also highly Danish Cancer Society, Institute of Cancer Biology
likely that genes are identified in this project will be candidate targets
for the development of novel cancer therapies.The development of such Copenhagen, Denmark
therapies lies outside the time-frame and scope of the proposal. Thiery, Jean Paul
CNRS UMR 144,
Wholemount staining of the epithelial ductal structure in a mouse Institut Curie, Cell Biology Department
mammary gland.The lymph nodes are also visible as densely-stained Paris, France
spheroidal structures. Georg-Speyer-Haus
Frankfurt am Main, Germany
Nol,Agns
Laboratoire de Biologie des Tumeurs et du Dveloppement
Lige, Belgium
Collard, John
The Netherlands Cancer Institute, Division of Cell Biology
ten Dijke, Peter
The Netherlands Cancer Institute
Division of Cellular Biochemistry
Stauber, Roland
Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus,
Paul-Frankfurt am Main, Germany
Acronym: BRECOSM
Project number: LSHC-CT-2004-503224 Zollo, Massimo
EC contribution: 3 430 273 TIGEM-Telethon
Duration: 36 months Naples, Italy

213
CANCER MetaBre
Molecular Mechanisms involved in organ-specific

Metastatic growth process in Breast Cancer
Summary
MetaBre is a EU-funded research project that aims to
identify the underlying mechanisms that cause metastasis
in breast cancer.There has been considerable success in
the treatment of breast cancer in recent years,if detected
in its early stages.However,breast cancers are very prone
to metastasise, and cause secondary tumours in bone,
liver, lungs, brain and lymph nodes. Once solid metastatic
tumours are established, the likelihood of complete
remission falls, and patients can suffer symptoms
generated by metastases that affect quality of life.
More than 200,000 women are diagnosed in Europe

every year.
Main group, L to R: Roberto Buccione, Olivier de Wever, Pavel Gromov,Anna Teti, David
Lifetime risk of developing breast cancer is 1 in 10. Waltregny, Keltouma Driouch, Michael Baldwin,Akeila Bellahcene, Gabri van der Pluijm,
Nadia Rucci, Philippe Clement-Lacroix, Sue Eccles, Marc Bracke, Rosette Lidereau,Vincent
It is the leading cause of death in women between ages
Castronovo,Angels Sierra, Ben-Tsion Williger, Rachel Klein, Rita Paro.
35 to 55. Insets L to R: Lenaic Paon,Verena Collazo, Nick Henriquez Philippe Clezardin., Richard
Metastasis in breast cancer is a complex multistep process. Bachelier, Philippe Pujuguet, Marcela Chavez, Maciej Ugorski,Anna Laskowska
not pictured:,Thomas Landemaine
Genetic changes in tumour cells give rise to aggressive
metastatic cells, and these home in on specific organs
because of a complex web of molecular and matrix interactions with
Expected results
the organ microenvironment. Understanding the key molecular MetaBre has research activities aimed at:
mechanisms of these metastatic processes can lead to improvements in gene profiling and proteomic analysis to identify new molecular
the prognosis and treatment of breast cancer patients. targets
functional analysis of new targets in in vitro and in vivo models
Aims mechanisms of angiogenesis and invasion
MetaBre will aim to discover new gene and protein markers that can organ-cancer cell interactions
be used for diagnosis as a signature of metastasis to specific organs,
development of new pharmacological therapies and diagnostic
and also can be targets for therapy.
techniques
To achieve this, the partners will analyse samples of breast tumours
preliminary clinical trials.
and metastases, with due care of the ethical aspects, as well as
established breast cancer cell lines. MetaBre will use state-of-the-art Affymetrix chips for gene
profiling and will develop novel in vitro and in vivo models for
MetaBre will also study genes and molecules that are already
validation of molecular targets and screening of therapeutic
suspected of involvement in metastasis.This builds on previous work
molecules.
of the partners and will enhance understanding of the role of these
molecules in metastasis, as well as identifying new therapies and Metastases will be detected in vivo with optical imaging of luciferase-
diagnostic methods against these targets. expressing cancer cells and magnetic resonance techniques.

214
CANCER
Progress LUMC are working on some innovative tools for studying of gene
expression in in vitro and in vivo models.They are also working towards
The MetaBre kick-off meeting (below) was successfully organised a 3D model of epithelial-mesenchymal transition in breast cancer.
in February 2004 and received regional and national media coverage
Partner CMNS is studying the basic cell biology of MMP trafficking,
in Italy. As well as the MetaBre partners, the meeting was also
and has also started work with UNIVAQ on the characterisation
attended by Dr Pavel Gromov of the Danish Cancer Society who
of the podosomes features of osteoclasts that are involved in the
will advise on the proteomics research.
development of bone metastases through degradation of bone
The research activities in the project include identification of new matrix. These may be similar or even identical to invadopodia of
genes and proteins involved in molecular mechanisms of metastasis cells involved in degradation of extra-cellular matrix.
in breast cancer, as well as work on targets already identified. To
ICR are working to understand molecular mechanisms of metastasis
assist the collaboration, inventories of cell lines and in vivo models
to lymph nodes and have been testing cell lines for expression of
available among the partners have been compiled.
factors that are suspected of involvement. Work has started with
There was a strong emphasis in the first year of MetaBre on organising a 3D epithelial cell culture and ICR will use microarrays to identify
collection of tissue samples that will be used in gene profiling and genes upregulated when cancer cells interact with the lymphatic
proteomics work. Partner CRH is leader of this work package and endothelium.
they have supplied a number of tissue samples of liver and lung
A number of new therapeutic approaches are being tested already in
metastases, and primary breast tumours from their own collection.
the project, against known molecular targets. UNIVAQ has built on
Several other partners have access to tissue banks and clinics and have
previous work on the role of c-Src in the development of bone
also collected tissue samples. A meeting of the partners involved in
metastases. New results from in vivo experiments show that c-Src
gene profiling was arranged in Paris in April 2005, and a common
specification sheet has been prepared.CRH collated the data on tissue
samples into a confidential database.
The gene profiling has mainly used the Affymetrix platform
provided by partner PSK, but the partners will also use other
microarray systems in order to maximise the opportunities for gene
profiling in the project. The first gene profiling with Affymetrix
has been completed on a breast cancer cell line sub-clone B02
developed by partner INSERM that strongly metastasises to bone.
This has generated interesting results that are being analysed by all
partners. Currently samples of clinical bone metastases are being
collected in order to validate these data. Also analysis was
successfully performed on liver and lung metastases and primary
breast tumours, though good quality RNA was not extracted from
all samples. Further analysis and comparison of gene profiles should
identify genes of interest. Functional analysis will follow.
Partner IRO has worked on identification of protein markers of organ-
specifity,particularly in lung and brain metastases.A number of proteins
have been identified from analysis of organ-specific breast cancer cell
lines, and these are being characterised and verified. For proteomic
analysis,advanced methods are being implemented to obtain accurate
results from smaller quantities of material.
Partner WAU is investigating the role of carbohydrate antigens in
breast cancer metastasis.So far no suitable cells lines have been found
as models of the Sialyl LewisX antigen known to be found in 30-40%
of breast cancers, so WAU aim to develop a modified cell line for this
purpose. In comparison,TF-antigen is expressed in most cell lines and
experiments are progressing with gene silencing using siRNAs. ULg
is also using siRNAs to silence histone deacetylases, which are Image of a bone metastasis obtained by
suspected to have a role in angiogenesis in breast cancer, for study 3 dimensional computerised micro-tomo-densitometry
with in vitro and in vivo models.

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CANCER
In MetaBre, metastases will be

detected in-vivo with optical imaging Coordinator
of luciferase-expressing cancer cells Prof.Teti,Anna
and magnetic resonance techniques Department of Experimental Medicine
University of LAquila
Via Vetoio Coppito 2
inhibitors have a significant effect on the incidence and growth of bone
67100 LAquila, Italy
metastases. Also INSERM has found new evidence of interactions
between breast cancer cells and blood platelets that stimulate bone Phone: + 39 0862 433511
resorption in osteolytic bone lesions. Fax: +39 0862 433523
Image of a bone metastasis obtained by three-dimensional E-mail: info@metabre.org
computerised micro-tomo-densitometry INSERM is testing Project web-site: www.metabre.org
endogenous anti-angiogenic agents such as thrombospondin.These Key words: Breast cancer, metastasis, gene profiling,
have been transfected into the B02 cell line to assess their effect organ-specific
on the growth of bone metastases in-vivo. Also PSK are testing new
compounds that inhibit an adhesion molecule, known to be
important for the vicious circle between breast cancer cells and Partners
osteoclasts. In vivo bioluminescent imaging has been used to detect Dr. Buccione, Roberto,
bone metastases at an early stage, thus permitting short-duration
Consorzio Mario Negri Sud (CMNS), Italy
in vivo experiments.
Dr. Lidereau, Rosette
Many of the molecular targets of MetaBre will be suitable as
Centre Rn Huguenin (CRH), France
prognostic markers.The University of Ghent has already identified
the soluble extra-cellular fragment of N-cadherin as a marker of Dr. Clezardin, Philippe
invasive breast cancer and is developing an ELISA assay for accurate INSERM U664, France
and rapid detection. This has involved development of suitable Dr. Clement-Lacroix, Philippe,
monoclonal antibodies and recombinant sN-cadherin for calibration
ProSkelia SaS (PSK), France
of the ELISA. Tests with serum samples from patients have
commenced. The sN-cadherin marker is useful not only for Dr. van der Pluijm, Gabri,
following progress of breast cancer treatment but also for other Leiden University Medical Centre (LUMC),
diseases. The Netherlands
IRO has also commenced work on magnetic resonance imaging and Dr.Williger, Ben-Tsion
magnetic resonance spectroscopy for detection of brain metastases. CancerTek Pharmaceuticals Ltd (CTP), Israel
This is useful for non-invasive measurement of experimental
Prof. Ugorski, Maciej,Wroclaw
metastases in vivo and also may ultimately have a clinical application.
Agricultural University (WAU), Poland
The project has received good publicity through two press
Dr. Eccles, Suzanne,
conferences in Italy and Belgium, and being profiled in Quest
magazine in December 2004. A website has been developed as well Institute of Cancer Research (ICR), United Kingdom
as a project flyer. Some of the project partners attended the Dr. Sierra, Angels,
Metastasis Research Society meeting in September 2004 and a high- Institut de Recerca Oncologica (IRO), Spain
profile presentation is planned for a major European breast cancer
Prof. Bracke, Marc,
conference in 2006.
Ghent University (UGent), Belgium
Prof. Castronovo, Vincent,
University of Lige (ULg), Belgium
Acronym: MetaBre
Duration: 36 months

216
ENACT CANCER
European Network for the identification and validation

of antigens and biomarkers in cancer and their
application in clinical cancer immunotherapy
Summary Aim
Prospective clinical material will be collected during the life of the ENACT aims to identify markers of response and tumour antigens
that associate with ovarian, breast and prostate cancer and
programme and new and existing tumour tissue, PBMC and serum melanoma progression and resistance to immunotherapy. The
banks will be available for use in the study.This common resource of present application will address these issues in a number of ways
material will be distributed to partners for the immunological,genomic, and directly analyse the important biomarkers that are expressed
by cancer and may therefore be considered as novel targets by
biochemical and proteomic analysis of tumour and host response(s) to
establishing a European network for collaboration.The cancer types
immunotherapy.The results will be subjected to bioinformatic analysis to be included will address the issue of sex-related biomarkers
in the context of clinical outcome of vaccine-based immunotherapy associating with resistance to therapy. Cell biological, immunological,
biochemical and molecular biology-based technologies will be used
trials from five European clinical centres.Analysis of the results in the
and knowledge generated in this project will not only result in a
context of gender will allow prominent inter- and intra-tumour / host desired and highly competitive technological base for vaccine
biomarkers to be identified for translation back into clinical practice. development (not necessarily restricted to cancer vaccines), but also
will provide a better understanding of basic biological mechanisms
underlying antigen presentation and recognition of tumours by
Problem CD8+ and CD4+ T lymphocytes and NK cells.
Cancer remains a major health problem, with untold physical,
psychological and economic costs to society. Elimination of cancer Expected results
would reduce health care costs and enhance quality of life. Along
with cardiovascular disease and ageing, it is currently the most 1. to establish a database for the analysis of clinical and experimental
intractable source of suffering and health care cost. Recent results results in order to identify markers related to the outcome of
from immunotherapy trials would suggest that inducing tumour- immunotherapy
specific T-cell responses to tumour antigens can, in some patients,
2. to provide clinical material and cancer cell lines for scientific
cause the regression of tumours or the stabilisation of the disease.
investigation conducted within the programme
However the mechanisms underlying the failure of immunotherapy
to control and destroy residual cancer remains to be fully 3. to assess the cellular and humoral immune response in patients
established. Experimentally, it can be shown that tumour rejection undergoing immunotherapy
is mediated by CD8+CTLs aided by CD4+T-helper cell activity.
4. to identify biomarkers using proteomics and computer based
However animals that fail to respond may fail to demonstrate a
algorithms
pronounced (if any) CTL response. In addition data from many
laboratories have shown that tumour escape from CTLs can occur 5. assessment of the importance of immunological, genetic and
as a result of downregulation of MHC class I antigens, and in some proteomic biomarkers as indicators of therapeutic response related
instances cancer cells that show successive mutations may to gender
demonstrate progressive and complete loss of MHC expression.The
6. dissemination of the information to the scientific community and
current status of our understanding of adoptive cancer immunity
the community at large.
also suggests that immune tolerance can equate with lack of
response, with possible regulation by CD4+CD25+T-lymphocytes
as well as other regulatory cells. Breaking tolerance through
immunotherapy therefore represents one possible approach to
promote T-cell responses and tumour regression.

217
CANCER
Coordinator
The use of therapeutic cancer vaccines still has to be firmly established
and previous clinical trials strongly indicate that not all patients benefit Prof. Rees, Robert
from receiving such treatment. The present study will allow us to Interdisciplinary Biomedical Research Centre
establish whether the results of ENACT can be used in a clinical Nottingham Trent University
setting. The identification of indicators of patient response to
immunotherapy would allow clinicians to target vaccination to those Faculty of Science and Land Based Studies
patients who are most likely to respond.The findings of the present School of Science
study could result in assays that could be used to predict treatment
Clifton Lane
outcome and / or monitor patients during the course of treatment.
This would benefit the health care industry and patient care and the Nottingham, NG11 8NS, United Kingdom
findings may be applicable to cancers other than those included in the E-mail: robert.rees@ntu.ac.uk
research programme. The approach will allow us to gain further
Project web-site: https://www.enactcancerresearch.org
scientific understanding of the immune response to tumour antigens,
which may influence the development of future generations of cancer Key words: Tumour progression, biomarkers, tumour
vaccine.This research represents a valuable contribution to the welfare escape, melanoma, prostate cancer, ovarian cancer
of patients who would be considered to be suitable candidates for
vaccine-based therapy.
Partners
Laboratory of Clinical Immunology, University Hospital,
Sofia, Bulgaria
Abt.Innere Medizin II Zentrum fur Medizinische
Forschung, ZMF, Universitatsklinikum Tuebingen, Germany
Department of Oncology-Pathology, Karolinska Institute,
Stockholm, Sweden
INSERM U463, Institue de Biologie, Nantes, France
Institute of Medical Biochemistry, Jagiellonian University
Medical College, Krakow, Poland
Biomedical Research Study Centre, University of Latvia,
Riga, Latvia
Departamento de Analisis Clinicos, Hospital
Universitario, Granada, Spain
Skin Cancer Unit (DO70), University Hospital Mannheim,
Germany
Department of Immunology, Institute for Cancer
Research, Section for Immunotherapy,The Norwegian
Radium Hospital, Oslo, Norway
The Anthony Nolan Research Institute,The Royal Free
Hospital, London, United Kingdom
Loreus Ltd, Nottingham, United Kingdom
Dept. of Immunology, Hellenic Anticancer Institute,
Athens, Greece
Onyvax Ltd, St Georges Hospital Medical School,
Acronym: ENACT
Duration: 36 months

218
PROTHETS CANCER
Prognosis and therapeutic targets in the Ewing

family of tumours
Summary a.The histogenesis of ESFT is still uncertain and the normal
counterpart of ESFT cells is still unknown.
The project through collaborative studies will define prognostic b.The lack of prognostic factors obliges the use of non-differentiated
markers and new therapeutic targets in the Ewings sarcoma family treatments for all patients, leading to over-treatment of those
of tumours (ESFT) to provide rigorous scientific justifications for the patients who could benefit from less toxic therapies.The reduction
of delayed side-effects is particularly important in this disease
development of clinical trials for this rare disease, which is mainly considering the young age of the patient and their long life
manifested in children.The main objective of this project is to evaluate expectancy.
the prognostic relevance of selected markers (EWS/FLI-1, secondary c. In the current state of ESFT treatment there is a survival plateau
genetic alterations, CD99, IGF-IR, NOVH, erbB-2 and TTF1) and the (around 60% for patients with localised disease and 25% for high-
effectiveness of therapeutic approaches targeting some of these risk groups) due to the lack of new drugs and toxicity that impedes
more intense use of existing drugs. The identification of new
molecules. Another major goal of the project is the construction of targets for innovative therapeutic strategies is, therefore, strongly
ESFT c-DNA microarrays and tissue arrays, which will be used for needed for this tumour.
the analysis of different histological subtypes of ESFT, primary and Progress is generally hampered by the rarity of the disease (in Europe
metastatic tumours and poor and good responders to chemotherapy. about 400 cases/year) implying a limited number of cases for effective
research. Moreover, because ESFT is an orphan disease, no private
This will lead to: 1) the definition of forthcoming risk-adapted
company will develop new therapeutic tools and take on the costs
strategies and targeted molecular treatments to be advantageously to conduct pre-clinical investigation.
combined with established therapies; 2) improved quality of life and
survival for ESFT patients; 3) prevention on risk in groups at risk. Aim
The project will define prognostic markers and new therapeutic
Problem targets in the Ewings sarcoma family of tumours (ESFT) through
The Ewings sarcoma family of tumours (ESFT) includes: Ewings collaborative studies to provide rigorous scientific justification for
sarcoma; primitive neuroectodermal tumour; Askins tumour; the development of new therapeutic strategies for this rare disease,
paravertrebral small-cell tumour; atypical Ewings sarcoma. ESFT which is manifested for the most part in children. Goals expected
represents a peculiar entity in oncology. In spite of its absolute rarity to be achieved:
(about 300-400 cases per year in Europe), ESFT is one of the most 1.With respect to the problem of toxicity, the project, by identifying
frequent solid neoplasm in paediatric age groups. Due to this fact, its the clinical relevance of a number of markers, may allow the
impact on the health system is particularly important.The adoption differentiation of patients in terms of risk to recur.This will enable
of multimodal treatments with very aggressive chemotherapeutic more aggressive treatments where these are justified, and avoid
regimens have significantly improved the chance of survival of ESFT toxicity in cases where such treatments may be known to be
non-metastatic patients, shifting the five-year survival rates to around unnecessary, with particularly significant consequences for the
60%.Despite these important clinical results,which are usually difficult quality of life of the patients.
to obtain in rare diseases, several problems related to histogenesis,
prognosis and treatment response are still open. In particular: 2. Successful treatment of therapy-resistant patients requires new
strategies. Indeed, there is a desperate need for new therapeutic
approaches in ESFT. A thorough study of the pre-clinical
effectiveness of new targeted therapeutic strategies will be
performed with the aim of the identification of the Achilles heel
in this disease and the consequent development of a tailored
biological therapy to be used in association with conventional
chemotherapy.
3. By providing an organisational framework for collaboration the
project will also allow multi-centre collection and analysis of cases
as well as suitable collaborative research to allow genetic studies
Histological features of for the screening of high-risk patients and patients responding
Ewings sarcoma: stain for CD99
Ewings sarcoma differently to chemotherapy.

219
CANCER
Expected results on the biomedical world. Specified actions of the project are devoted
to dissemination activities to ameliorate harmonious relations
1.The identification of prognostic factors in ESFT as a basis for the between cancer researchers and society, with particular regard to
definition of individual therapeutic regimens, which would limit the patient associations.
incidence of acute side-effects and long-term morbidity as well as
the economic and social consequences of intensive chemotherapy.
2.The definition of patient selection criteria to be used as a basis for Coordinator
beginning a pivotal clinical trial. Dr Picci, Piero
3.The creation of new therapeutic bullets against ESFT.They will be Department of Musculoskeletal Oncology I. F. Goidanich
available at the end of the project as new drugs for ESFT treatment, Istituti Ortopedici Rizzoli
together with the required toxicological and pharmaco-kinetics
Via di Barbiano 1/10
studies.This is an important point because ESFT is an orphan disease
and no private company will develop new therapeutic tools and take 40136 Bologna, Italy
on the costs of conducting pre-clinical investigation. Phone: + 39 051 6366759
4. New therapeutic strategies for oncologists to increase the survival Fax: + 39 051 582244
rate of ESFT patients through the pre-clinical evaluation of new E-mail: piero.picci@ior.it
drugs and strategies based on an immunological approach. Project web-site: under construction
5. New clues in the diagnosis and the screening of high-risk groups (www.prothets.org).
through the creation of an extensive tissue bank and the genetic profile There will be a link in: http://www.ior.it.
analysis (cDNA microarray and tissue array analyses) of these samples. Key words: Ewings sarcoma, EWS/FLI1, CD99, insulin-
like growth factor, microarrays
Partners
Therefore the project,aiming to ameliorate treatment of ESFT,will have
an impact on child health.In particular,the main objective of this project Laboratory of Oncologic Research, Istituti Ortopedici
is to develop patient-oriented strategies for Ewings sarcoma patients Rizzoli, Bologna, Italy
by: a) integrating different disciplines and advanced technologies to Institut National de la Sant et de la Recherche Mdicale,
develop effective approaches or new tools for diagnosis, prognosis and Nice, France
treatment. b) elucidating the contribution of specific molecular and Laboratory for Experimental Orthopaedic Research,
genetic factors to the histogenesis of the disease. University Hospital of Mnster, Germany
This work will unlock the potential of the individual studies carried out Haartman Institute, Department of Medical Genetics,
by each of the consortium partners, and it will define targeted University of Helsinki, Finland
therapeutic strategies of practical value in clinical settings and the clinical Department of Pathology, Medical School, Hospital
relevance of a number of markers that will allow the differentiation of Clinico Universitario,Valencia, Spain
patients in terms of risk of recurrence. It will also unlock the biological
Laboratory for Molecular Biology, Childrens Cancer
and clinical information potential behind multi-centre data collection
Research Institute, St. Anna Childrens Hospital,Vienna,
and genetic analysis of patients, bringing basic knowledge to the
Austria
application stage. Progress is generally hampered by the rarity of the
disease, implying a limited number of cases for effective research.The Universit Paris 7 Denis-Diderot, Paris, France
creation of a multi-centre tissue bank and data collection will help to Centre National de la Recherche Scientifique, UMR8121
overcome a big obstacle.The application of new technology will be used CNRS Institute Gustave Roussy PR2,VilleJuif, France
to identify ESFT-related molecular mechanisms. The gene expression Belozersky Institute of Physico-Chemical Biology,
profile of ESFT will be analysed and new markers to be used for Moscow State University, Russia
diagnostic, prognostic and therapeutic purposes will be identified.
GenX Laboratories srl,Vignate, Italy
The project made efforts in the integration of multi-disciplinary research Mabgne S.A., Ales, France
capacities across Europe. The consortium includes pathologists,
oncologists, immunologists, and molecular and cellular biologists.
Moreover, PROTHETS lays emphasis on collaboration with small and
medium-sized enterprises (SMEs),devoted to the development of specific Acronym: PROTHETS
tools for prognostic and therapeutic applications. Project number: LSHC-CT-2004-503036
Finally, the development of evidence-based guidelines will ensure that Instrument: Specific Targeted Research Project
the knowledge held and developed by and within the project will be Duration: 36 months
distributed as widely as possible to have the highest possible impact

220
P-MARK CANCER
Validation of recently developed diagnostic and

prognostic markers and identification of novel markers
for prostate cancer using European databases
Summary promising markers. Novel serum and urine markers will be identified in
clinically well-defined biomaterials using innovative mass spectrometry
The current diagnostic markers for prostate cancer have a low tools, and antibody-based immunoassays will be developed for these
markers.The novel markers will be evaluated for their clinical importance
specificity and lead to over-diagnosis and over-treatment due to the
using these assays. Recently developed promising markers that prove
detection of small non-aggressive or non life-threatening cancers. In their clinical value during the evaluation will be validated on a sample
addition, there are currently no efficient serum or urine markers set derived from two European screening studies (the ERSPC study and
the ProtecT study). Eventually, the markers arising from this project will
available for the prognosis of this malignancy.The P-Mark project will
be offered to SMEs for commercialisation and to ongoing large European
address the growing need for improved diagnostic and prognostic clinical studies for clinical implementation.
markers for prostate cancer.
Expected results
Problem 1. the establishment of a serum biorepository and a urine
In Europe, prostate cancer (Pca) is the second most frequent lethal biorepository for the discovery, evaluation and validation of
malignancy in men. Yearly about 40 000 men die of Pca in the EU diagnostic and prognostic Pca markers
countries.There is a slow increase of mortality and in addition, due to
2. the discovery of novel Pca markers in human body fluids by
an ageing population, a 50% increase in incidence is expected by 2020.
innovative mass spectrometry tools
So far,the only chance for cure is early detection and treatment by either
surgery or radiotherapy.Diagnosis of Pca is made by ultrasound guided 3. the establishment of the clinical utility of recently developed
transrectal biopsy of the prostate for histology. An increased level of promising Pca markers, including PCA3DD3, bone morphogenetic
the serum marker prostate specific antigen (PSA) predominantly protein-6 (BMP-6), osteoprotegerin (OPG), nicked PSA, human
indicates such a biopsy.A major disadvantage of this diagnostic marker kallikrein 2 (hK2) and cytochrome P450 3A5*3 polymorphism
is its low specificity, resulting in a significant amount of false biopsy (CYP3A5*3)
indications.PSA is a normal excretion product of the prostate cells and 4. the validation of Pca markers and identification of risk groups in
is therefore not only found in the circulation of men with prostate the general population in Europe
cancer but also of men with a normal prostate and men with benign
prostatic hyperplasia, a phenomenon that is associated with ageing. 5. the development of guidelines for cost-efficient strategies for Pca
Nevertheless,PSA is the standard marker for Pca diagnosis and has been detection and therapy.
demonstrated to be effective in advancing the diagnosis by detecting
Pca at earlier stages.A growing number of men choose to be screened
for Pca by PSA analysis,even up to 60-70% of men in the USA.However,
the value of screening for Pca has not been established yet and is
currently the subject of investigation in the European Randomised Study
of Screening for Prostate Cancer (ERSPC). A major drawback of the
standard diagnostic tools for Pca is the detection of small non-aggressive
or non life-threatening cancers, leading to over-diagnosis and over-
treatment, as well as the detection of tumours that are too advanced
to cure. Currently, there are no serum or urine markers available for
the prognosis of Pca at early disease stages apart from PSA.It is apparent
that improved diagnostic and prognostic serum or urine markers are
required that can discriminate men with clinically irrelevant Pca,curable
Pca, or life-threatening Pca.
Aim
For three years, P-Mark will search for improved diagnostic and
prognostic Pca markers by the identification and evaluation of novel
markers as well as the evaluation and validation of recently developed

221
CANCER
Coordinator
P-Mark will evaluate the clinical value of recently developed promising
Pca markers and of novel Pca markers. If a marker meets the defined Prof. Bangma, Chris H
P-Mark marker criteria (improved sensitivity and specificity over Department of Urology
current markers for diagnosis or prognosis; indicative for early
detection, over-treatment, risk for progression or therapy resistance; Erasmus MC, room H1074
clinically relevant target in relation to tumour biology; reliable and Dr. Molewaterplein 40, 3015
cost-efficiently determinable in non-invasively obtained specimens;
stable component in specimen), it will be developed further for the PO Box 2040,
validation in a mono-centre or multi-centre setting. In addition, the 3000 CA Rotterdam,The Netherlands
marker will be offered to commercial enterprises for
commercialisation.Validation will lead to guidelines for cost-efficient Phone: + 31 10 463 3607
strategies for detection and treatment as well as recommendations Fax: + 31 10 463 5838
for marker application, that have to be discussed in the public domain
of related European professional societies.Validated markers will be E-mail: h.j.vanalphen@erasmusmc.nl
offered to the principal investigators of ongoing screening studies in Project web-site: http://www.p-mark.org
Europe for implementation in the study.Taken the duration of P-Mark
into consideration (three years), clinical marker implementation will Key words: prostate cancer, markers, diagnosis, progno-
continue beyond this project. sis, serum, urine, proteomics, mass spec-
trometry
Partners
Department of Laboratory Medicine, Division of Clinical
Chemistry,Wallenberg Laboratory, University Hospital
Malm, Sweden
Department of Urology, University Hospital Malm,
Sweden
Department of Experimental Urology, University of
Department of Urology, University of Sheffield, United
Kingdom
Department of Clinical Chemistry, Helsinki University,
Central Hospital, Finland
Department of Biotechnology, University of Turku,
Finland
Centre for Pharmacy, Analysis of Biomacromolecules,
University of Groningen,The Netherlands
Innotrac Diagnostics OY,Turku, Finland
CanAg Diagnostics AB, Gteborg, Sweden
Acronym: P-Mark
Duration: 36 months

222
EUSTIR CANCER
A European strategy for the integration

of research on breast cancer
Summary Problem
The overall objective is to create a permanent European overview The present methods of awarding research grants in cancer suffer
from many defects and appear to result in repetitive research, often
process for the award, audit and recording of all research on breast with no clear result and no clinical relevance.There is no agreement
cancer: This will be the creation of the funding bodies themselves as to which areas are the most important, there is no attempt to
which, for each project, will retain the absolute power of award. ensure claims are validated,there is no audit process for success/failure
and no ranking of ability of individual units to complete projects and
The project aims to create: their value.This means that monies for research are often spent poorly.
1.A European overview process for project proposals received by all

Aim
funding bodies.This will
1. LONG TERM AIMS
i) prevent research from being funded for similar work in multiple
projects To harmonise breast cancer research through individual funding
organisations operating within Europe
ii) result in a few large, rather than multiple small series, which are
To encourage research to be focused on that which will have ultimate
much more likely to yield definite results.
clinical application
2.A body of the leading researchers in breast cancer which agree the To ensure that validation is a part of the design of all applications
areas most likely to give results of clinical relevance and agree To establish an audit system backed by a database that allows
certain issues that must be included in all proposals (such as assessment of the success rate of individual research groups.
validation of the results). 2. PROJECT SPECIFIC AIMS
3.An audit process of research work.This addresses the problem that To bring together all organisations involved in developing,supporting
and undertaking breast cancer research in Europe to design a
many projects do not address their aims.The audit outcomes will
strategy for the pan-European harmonisation of breast cancer
be accessible to research funders, so that institutes most likely to research.
complete valuable projects are identified (and the converse!).This To develop a process of audit of completed research whereby research
project will be divided into 3 parts; i) a workshop of leading projects will also be judged as to whether they have advanced the
European research workers in breast cancer to define the most science and to what degree they are relevant to clinical practice.
important areas for research and to make suggestions on an To maintain a database of projects and of the audit of completed
projects
overview process ii) a workshop of the funding organisations &
Audit of past projects and production of a policy paper for
other interested parties to discuss and agree a strategy for
implementation
harmonising research in the identified areas and iii) validation of
To influence journal editors, to ensure higher standards are set for
projects funded to date against criteria established within the acceptances for publication of results; validation and clinical
project. relevance will be the most important issues.

223
CANCER
Expected results
A European overview process for project proposals received by all Coordinator
funding bodies.This will
i) prevent research from being funded for similar work in multiple Prof. Roger Blamey
projects Breast Institute
ii) result in a few large, rather than multiple small data sets, which Nottingham City Hospital NHS Trust
are much more likely to yield definitive results
Hucknall Road
2.Agreement and ranking of the areas most likely to give results of
clinical relevance. Nottingham NG5 1PB, United Kingdom
3.Agreement on certain issues that must be included in all proposals Tel: +44 115 962 5707
(such as validation of the results) Fax: +44 115 962 7765
4.An audit process of the results of funded research.This will initially Email: wbartlanm@ncht.trent.nhs.uk
show if the contentions expressed above with regard to funded
research, are in fact correct.The audit outcomes will be accessible Key words: breast cancer, funding, harmonisation
to research funders, in that institutes most likely to complete
valuable projects will be identified (and the converse!).
Potential applications Acronym: EUSTIR

Project number: LSSC-CT-2005-517659
Aside from the obvious and intended application in breast cancer EC contribution: 198 640
funding across Europe,the model created by the project can be applied Instrument: Specific Support Action
Duration: 24 months
to many funding areas where multiple sources of funding create the Starting date: 01/01/2006
same problems as seen in breast cancer.

224
EUROCAN +PLUS CANCER
Feasibility Study for Coordination of National

Cancer Research Activities
Summary A further obstacle is the lack of common core elements in the
curriculum of professionals.Common quality standards in training are
A key issue remains how effective coordination of Cancer Research in needed to facilitate the collaboration at European level as well as the
mutual recognition of the qualifications between European countries
Europe can see the European Union (EU) benefit from the advantage
and therefore the mobility of researchers and physicians.The situation
of scale, which its population provides. Cancer research in EU is is particularly exemplified by the absence of recognition of Oncology
fragmented and frequently duplicative. Resources are wasted and as a Medical discipline by many European countries and its variable
status in most Member States.
implementation of closer cooperation to develop a strategy for Cancer
Research by the Member States would clearly be cost-efficient and Consequently, although a large amount of financial resources is
involved, and a substantial portfolio of initiatives is carried out, cancer
hasten the development of major advances and their delivery to the
research efforts are not currently benefiting from the advantages that
population. Barriers to collaboration in cancer research need to be a coherent and more co-ordinated framework would bring about.
identified and ways sought to encourage the development of
collaborations in the Member States. Aim
On the basis of an overview as complete as possible of Cancer
Problem research in Europe, objectives of the project are to:
Cancer remains a major Public Health problem worldwide with 1. Identify the fields, topics and research subjects where the lack of
Europe hit hard and the situation set to worsen in absolute terms as co-ordination of national activities is particularly detrimental for
the population ages.Around one half of cancer patients still die from the progress of knowledge and the quality of care;
their disease. On the other hand, there are currently great
2. Identify those specific fields,topics and research subjects where the
expectations that we are on the brink of making huge progress against
awareness of the need, as well as the willingness and readiness to
the disease. Elucidation of the human genome and rapid advances in
achieve a better co-ordination, are established enough as to make
understanding details of its function allied to rapid progress in
such an achievement likely;
technology,gives great hope of rapid advances taking place.The current
era offers more real hope than any previous. 3. Explore the suitability, for this purpose, of the various support
schemes available in the 6th Framework Programme (Co-ordination
Cancer remains the subject of significant research effort at both the
actions; ERA-NET schemes;Article 169);
European level and in the Member States. Between 2002 and 2006, the
European Union will be devoting more than 435 Million to this field 4. Explore,in particular,the interest and feasibility of an initiative based
of research.This is in addition to national funding in Member States. on article 169 (participation of the EU into national research
programmes jointly implemented);
An important aim for the Commission is to achieve a better
framework for collaboration in cancer research in Europe, and there 5. Help determine the means by which further exploring the
is a recognition that coordination of national cancer research efforts possibilities and ways to progress in the direction of a better co-
at the European level is far from being achieved. Among the key ordination (study, workshop, conference, survey);
elements proposed to explain this situation are the barriers between
6. Give orientation on all the issues above raised and practical
disciplines and fields of research; the fragmentation of research
recommendations on the last points.
activities dedicated to the different types of cancer and the resultant
sub-optimal critical mass; the weakness of the links between basic,
applied and clinical research, leading to a rather limited integration of Expected results
basic and clinical research;and the implementation of all these activities
mainly in a national framework and a national context. As a The project shall provide key answers to the following questions through
consequence, Europe is unable to fully benefit from the advantage of the exploration of barriers to Research Collaboration in the EU in
scale afforded by its 500 million population. specific fields as well as by dealing with some of the key issues including
mobility of cancer research workers throughout the European Union:
Europe is at present, and has been for many years, unable to retain
many of its most talented scientists and is unable to provide a scientific Irrespective of the prospects generated by considerations of alternative
environment capable of attracting top young scientists from outwith legal, governance and financial matters, including article 169, what can
the continent. In addition, there is no national incentive to promote be done to facilitate Cancer Research in the European Research Area?
mobility within the Member States. Consequently, the development What could be done to enhance Cancer Research in the European
of transnational research activities is impeded by the obstacles to the Research Area by new application(s) of available legal, governance and
mobility of researchers. financial considerations, including Article 169?

225
CANCER
Potential applications University College Dublin

The project is certainly going to have a major impact on the structuration Dublin, Ireland
of Cancer Research,basic and clinical,throughout the EU.Furthermore,
the EU will dispose of concrete and practical recommendations for the Dr Jan-Willem Hartgerink
definition of priorities in research programmes. International Affairs Department
Ministerie van Volksgezondheild,Welzijn en Sport
The Hague,The Netherlands
Coordinator
Prof. David Kerr
Dr Peter Boyle
Department of Clinical Pharmacology
International Agency for Research on Cancer
The Chancellor, Masters and Scholars of the University
150 cours Albert Thomas of Oxford
69008 LYON
Radcliffe Infirmary
Tel.: +33 4 72 73 85 77
Fax: +33 4 72 73 85 64
Dr Peter Lange
E-mail: director@iarc.fr
Unterabteilung 61: Gesundheit, Biowissenschaften
Partners Bundesministerium fr Bildung und Forschung
Prof. Harry Bartelink Berlin, Germany
The Netherlands Cancer Institute Prof Jose Martin Martin-Moreno
Department of Radiotherapy Professor of Medicine and Public Health
The Netherlands Cancer Institute/ Medical School, University of Valencia
Antoni van Leeuwenhoek ziekenhuis Valencia, Spain
Amsterdam,The Netherlands Prof Herbert Michael Pinedo
Dr Filippo Belardelli VUmc Cancer Center Amsterdam
Department of Cell Biology and Neurosciences Amsterdam,The Netherlands
Istituto Superiore di Sanita' Ulrik Ringborg, MD, Ph.D.
Rome, Italy Radiumhemmet-Dept. of Oncology
Prof. Julio Celis Karolinska University Hospital Solna
Institute of Cancer Biology Stockholm, Sweden
Danish Cancer Society Prof. Dimitrios Trichopoulos
Copenhagen, Denmark Department of Hygiene and Epidemiology
Dr Diana Dunstan School of Medicine
MRC Research Management National and Kapodistrian University of Athens
UK Medical Research Council Athens, Greece
London, United Kingdom Prof Thomas Tursz
Prof. Alexander M.M. Eggermont, MD, PhD Direction Gnrale
Surgical Oncologist Institut Gustave Roussy
Erasmus University Medical Center Villejuif, France
Department of Surgical Oncology

Erasmusc MC - Daniel Den Hoed Cancer Center
Acronym: EUROCAN+PLUS
Rotterdam,The Netherlands Project number: LSSC-CT-2005-015197
Prof. John M Fitzpatrick Instrument: Specific Support Action
Surgical Unit- Mater Misericordiae Hospital Duration: 24 months
Starting date: 2005

226
Indexes
Acronym 228
Contract number 230
Coordinator 232
Index by acronym
ActinoGEN 70 eTUMOUR 198
Active p53 170 EUGENE 236
AGEACTION 156 EUGINDAT 58
AMIS 77 Eumitocombat 44
ANABONOS 152 EURAPS 60
Angiotargeting 166 EUR-INTAFAR 68
APOPIS 93 EUROCAN + PLUS 225
AUTISM MOLGEN 106 EuroClot 26
AUTOROME 62 Euroglycanet 47
BIOCARE 164 EUROHEAD 111
Bloodomics 18 EUROMEMO 132
BrainNetEurope II 102 European LeukaemiaNet 202
BRECOSM 212 European MCL Network 209
CANCERDEGRADOME 182 EUROSCA 97
CCPRB 196 EuroWilson 52
Cells into Organs 148 EUROXY 194
COBRA 82 EUSTIR 223
Diabesity 32 EVGN 20
DNA METHYLATION 206 EXGENESIS 34
ECRIN-RKP 14 FENS Forum 2004 137
Eicosanox 12 FIRST 179
EMBIC1 46 GEHA 144
EMIL1 73 GENADDICT 95
ENACT 217 GENESKIN 49
ESNI course 2003 135 GRIPANNT 124

228
IMMIDIAB 141 PROTHETS 219
INTACT 162 PWS 56
INTERDEVO 129 RABRE 139
LINK-AGE 150 SPASTICMODELS 113
MAESTRO 195 STRESSPROTECT 126
MetaBre 214 STROMA 185
micro-MATRIX 85 SYNSCAFF 108
MIMAGE 142 TONECA 39
MOL CANCER MED 191 TRANSBIG 200
MOLSTROKE 24 TRANSFOG 176
Mutp53 187 VIRGIL 73
Myocardial Repair 28 X-ALD 120
NCL-MODELS 116
NeuroNE 100
NEWMOOD 90
Orphanplatform 64
OSTEOGENE 154
PainGenes 122
P-MARK 221
PNEUMOPEP 75
PREVIS 79
PRIMA 168
PROMEMORIA 88

229
Index by contract number
LSHC-CT-2003-502932 194 LSHM-CT-2003-502852 58
LSHC-CT-2003-503233 185 LSHM-CT-2003-502941 154
LSHC-CT-2003-503297 182 LSHM-CT-2003-503020 152
LSHC-CT-2003-504586 206 LSHM-CT-2003-503041 32
LSHC-CT-2003-506803 162 LSHM-CT-2003-503051 116
LSHC-CT-2004-502943 191 LSHM-CT-2003-503254 20
LSHC-CT-2004-502983 187 LSHM-CT-2003-503304 97
LSHC-CT-2004-503011 221 LSHM-CT-2003-503330 93
LSHC-CT-2004-503036 219 LSHM-CT-2003-503335 82
LSHC-CT-2004-503094 198 LSHM-CT-2003-503382 113
LSHC-CT-2004-503216 202 LSHM-CT-2003-503413 79
LSHC-CT-2004-503224 212 LSHM-CT-2003-504468 148
LSHC-CT-2004-503306 217 LSHM-CT-2004-005033 12
LSHC-CT-2004-503351 209 LSHM-CT-2004-005139 129
LSHC-CT-2004-503426 200 LSHM-CT-2004-005166 95
LSHC-CT-2004-503436 179 LSHM-CT-2004-005206 24
LSHC-CT-2004-503438 176 LSHM-CT-2004-005224 70
LSHC-CT-2004-503465 196 LSHM-CT-2004-005264 62
LSHC-CT-2004-503564 195 LSHM-CT-2004-005268 26
LSHC-CT-2004-503569 173 LSHM-CT-2004-005272 34
LSHC-CT-2004-503576 170 LSHM-CT-2004-005310 126
LSHC-CT-2004-504587 168 LSHM-CT-2004-502800 122
LSHC-CT-2004-504743 166 LSHM-CT-2004-502987 120
LSHC-CT-2004-505785 164 LSHM-CT-2004-503038 118
LSHC-CT-2004-506049 214 LSHM-CT-2004-503039 102

230
LSHM-CT-2004-503116 44 LSHM-CT-2005-512136 56
LSHM-CT-2004-503245 39 LSHM-CT-2005-513866 150
LSHM-CT-2004-503270 144 LSSC-CT-2005-015197 225
LSHM-CT-2004-503359 73 LSSC-CT-2005-517659 223
LSHM-CT-2004-503430 52 LSSM-CT-2003-502801 85
LSHM-CT-2004-503474 90 LSSM-CT-2003-502993 135
LSHM-CT-2004-503485 18 LSSM-CT-2003-503373 132
LSHM-CT-2004-504837 111 LSSM-CT-2003-504752 131
LSHM-CT-2004-504839 41 LSSM-CT-2004-005100 137
LSHM-CT-2004-511963 14 LSSM-CT-2004-503246 64
LSHM-CT-2004-511995 108 LSSM-CT-2004-511992 28
LSHM-CT-2004-512013 36 LSSM-CT-2005-013043 139
LSHM-CT-2004-512020 142
LSHM-CT-2004-512039 100
LSHM-CT-2004-512040 146
LSHM-CT-2004-512093 77
LSHM-CT-2004-512138 68
LSHM-CT-2004-512158 106
LSHM-CT-2005-005223 60
LSHM-CT-2005-005320 124
LSHM-CT-2005-512012 88
LSHM-CT-2005-512053 156
LSHM-CT-2005-512099 75
LSHM-CT-2005-512117 49
LSHM-CT-2005-512131 47

231
Index by project coordinator
Adlkofer, Franz 93 Dillner, Joakim 196
Andrew, Peter W. 75 Dreyling, Martin 209
Aym, Sgolne 64 Durston,Anthony J. 148
Bailey,Anthony James 106 Dyson, Paul 70
Bangma, Chris H. 221 Ebbesen, Peter 194
Berger, Johannes 120 Edwards, Dylan 182
Bjerkvig, Rolf 166 Fawcett, James 100
Blamey, Roger 223 Ferrari, Michel 111
Blandino, Giovanni 170 Foekens, John A. 206
Bock, Elisabeth 88 Franceschi, Claudio 144
Boyle, Peter 225 Frre, Jean-Marie 68
Brahme,Anders 164 Gautvik, Kaare M. 154
Brambilla, Riccardo 132 Giavazzi, Raffaella 185
Casari, Georgio 113 Gilhus, Nils Erik 135
Castro-Lopes, Jos 137 Gutmann, Laurent 82
Celda, Bernardo 198 Haeggstrm, Jesper Z. 12
Chaouat, Grard 146 Hardie, D. Grahame 34
Claussen, Bjrgulf 41 Hehlmann, Rdiger 202
Coppes, Rob 179 Helin, Kristian 162
De Libero, Gennaro 24 Henriques Normark, Birgitta 79
Deakin, Bill 90 Herdegen,Thomas 126
Demotes-Mainard, Jacques 14 Holland,Tony 56
Devor, Marshall 122 Jalanko,Anu 116
Di Luca, Monica 108 Kmpe, Olle 60
Dickson, Suzanne L. 32 Kirkwood,Thomas B.L. 156

232
Kitchen, Ian 95 Stuart, H. Ralston 152
Kretzschmar, Hans 102 Tanner, Stuart 52
Lenzen, Sigurd 39 Tavitian, Bertrand 173
Marn, Oscar 129 Tedgui,Alain 20
Matthijs, Gert 47 Teti,Anna 214
Newbold, Robert 191 Thiesen, Hans-Jrgen 62
Nicola, Jean-Philippe 195 Toussaint, Olivier 150
Olesen, Jes 139 van Strijp, Jos 77
Osiewacz, Heinz D. 142 Vicente, Miguel 85
Ouwehand,Willem H. 18 Villarroel,Alvaro 118
Palacn, Manuel 58 Wiman, Klas 187
Petter Ottersen, Ole 124 Zambruno, Giovanna 49
Piccart, Martine 200 Zoulim, Fabien 73
Picci, Piero 219
Rees, Robert 217
Resink,Thrse 24
Rie, Olaf 97
Roland, Per 131
Schalken, J.A. 168
Siminiak,Tomasz 28
Sleeman, Jonathan 212
Smeitink, Jan 44
Smith, Ulf 36
Spector,Tim 26
Storme, Guy 176

233
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Major Diseases Research - Catalogue of Research Projects (2003-2005)

RTD info is our quarterly magazine keeping you in touch with main developments (results, programmes, events, etc.). in the Sixth Framework Programme
It is available in English, French and German. A free sample copy or free subscription can be obtained from:
Luxembourg: Office for Official Publications of the European Communities
European Commission
Directorate-General for Research 2005 233 pp. 21.0 x 29.7 cm
Information and Communication Unit
ISBN 92-894-8153-6
-1049 Brussels
Fax (32-2) 29-58220
E-mail: research@cec.eu.int
Internet: http://europa.eu.int/comm/research/rtdinfo/index_en.html
EUROPEAN COMMISSION
Directorate F Health
Unit F.2 Major Diseases
Contact: Alain Vanvossel
European Commission
Office CDMA 2/22
B-1049 Brussels
Tel. (32-2) 29 62 578
Fax (32-2) 29 55 365
E-mail: alain.van-vossel@cec.eu.int
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Major Diseases Research Catalogue of Research Projects (2003-2005) in the Sixth Framework Programme
PROJECT SYNOPSES

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Cover-catalogue

Interested in European research? European Commission

Major Diseases Research - Catalogue of Research Projects (2003-2005)

Major Diseases Research

Edited by Alain Vanvossel

Directorate-General for Research

Europe Direct is a service to help you find answers

Freephone number (*):

Cataloguing data can be found at the end of this publication.

Luxembourg: Office for Official Publications of the European Communities, 2005

European Communities, 2005

PRINTED ON WHITE CHLORINE-FREE PAPER

Major Diseases Research (2003-2005)

Anti-Microbial Drug Resistance 67

Brain, neurological and psychiatric diseases 87

Human development and ageing 141

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005)

Important funded research projects in areas such as affective Acknowledgment

Major Diseases Research (2003-2005)

Eicosanoids and nitric oxide: Mediators of cardiovascular,

Major Diseases Research (2003-2005)

research to identify genes that participate in the biological

Major Diseases Research (2003-2005)

European Clinical Research Infrastructures Network

Major Diseases Research (2003-2005)

The development of Clinical Research Centres (CRCs) in Europe

Major Diseases Research (2003-2005)

Identification of risk genes for atherothrombosis in

Major Diseases Research (2003-2005)

Structure of the VWF-binding Coordinator

Major Diseases Research (2003-2005) 19

European Vascular Genomics Network

3) therapeutic angiogenesis,either conventional or cell-based to recover

Expression of the adhesion molecule VCAM-I (in brown) by the endotheli-

Major Diseases Research (2003-2005)

Atherosclerotic plaques (in red) at the surface of

Major Diseases Research (2003-2005) 21

c) Insufficient neoangiogenesis is an integral

Major Diseases Research (2003-2005)

Centre for Biopharmaceutical Sciences, University of

Major Diseases Research (2003-2005) 23

Molecular basis of vascular events leading

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005) 25

Genetic regulation of the end-stage clotting process

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005) 27

CARDIOVASCULAR Myocardial Repair

Clinical experience with bone marrow cells and

The researchers from participating centres have agreed to coordinate Aim

The current project of a Specific Support Action project is focused

Major Diseases Research (2003-2005)

Acronym: Myocardial Repair

Major Diseases Research (2003-2005) 29

Novel molecular targets for obesity and type 2 diabetes

Summary Expected results

Diabesity aims to combine neurophysiological, neuroanatomical, and 405 30 Gteborg, Sweden.

Major Diseases Research (2003-2005)

Major Diseases Research (2003-2005) 33

Health benefits of exercise: identification of genes