Call Identifier: EOI.FP6.2002
Investigation the genetic origin of IBD in an Expert Network

1.1
NEED & RELEVANCE: How the proposed research activities contribute to realising the
objectives of a priority thematic area and why it requires a European mobilisation of activities
and resources through the means of a Network of Excellence?
Aims and background
The proposed research activities of IBDEXPERTNET project fit into the priority research area 1.1.1.ii.a:
Application-oriented genomic approaches to medical knowledge and technologies - Combating
cardiovascular disease, diabetes and rare diseases. The other Sub-Thematic Priority is 1.1.2.i. Applied IST
research addressing major societal and economic challenges. In the creation of the European Research Area,
the implementation of shared cross boarder medical records for research and integration with bio-informatics
(DNA-microarrays and automated & customized microarray interpretation) will create a new way of working
to discover new IBD specific genes and proteomics for the benefit of the patient.
Both ulcerative colitis and Crohn disease appear to be more common in some industrialized countries such as
Scandinavia, United Kingdom, North America and less common in Central and Southern Europe, Asia and
Africa. Given data showing an increased incidence of ulcerative colitis in the United Kingdom, it is crucial
that more studies be conducted in developing countries. While the incidence of Crohn disease has increased
strikingly in many areas, the incidence of ulcerative colitis has remained fairly stable in most. This could be
due to the rising number of community-based studies, as well as the improved accuracy in diagnosing Crohn’s
disease. Although, the incidence of IBD among Blacks in Africa is low, infection rates are high, life
expectancy is lower than in developed countries. Data from the USA suggest that rates are similar in AfroAmerican and Caucasian populations. Rates for Jewish populations may be slightly higher than in non-Jewish
populations but this also varies geographically.
Recent epidemiological studies suggest that mortality rates for IBD are similar to that of the general
population for the majority of patients. However, older patients with IBD and newly diagnosed cases with
severe diseases are at increased risk of dying. There appear to be similar increased risks for developing colon
carcinoma and hepatobiliary carcinoma among patients with Crohn disease and UC. There is an increased risk
of developing rectal carcinoma in UC patients, an increased risk of developing carcinoma of the small bowel
in Crohn disease patients, and an increased risk of developing lymphoma among males with Crohn disease.
1.2
Expected outcomes
Genetic factors play an important role in the pathogenesis of IBD, including ulcerative colitis (UC) and
Crohn’s disease (CD). Evidence for genetic heterogeneity in IBD comes in part from the varying results of
genetic linkage mapping studies. These studies are considered a model for the search of genes in
multifactorial diseases. In the last decade several studies published about genetic heterogeneity in different
ethnic groups. The search for specific IBD susceptibility genes has been difficult due to complex genetic
factors, such as the absence of simple Mendelian inheritance patterns, incomplete penetrance, genetic
heterogeneity, and the inclement of more than one susceptibility of the involved genes. The other perplex
condition is the interaction among the immune system as the mediator of pathogenic mechanism, and the
intestinal flora as the contributor of the crucial immune stimulus. Based on genetic details of different ethnic
groups in different countries it could be great benefit to access that genetic knowledge and the related immune
reactions via a Network of Excellence and share the developed diagnostic methods (DNA sequencing,
microarrays, proteomic biochips) among the partners.
1.3
The added value of Europe
All the above listed factors are indicating a careful attention to genetic, environmental, and socio-economic
factors must be accounted for studies we are willing to perform in IBDEXPERTNET. It is necessary to
implement international collaborative studies using information technology tools (eForms and web electronic
patient records in the format of Hyper Text Markup Language HTML/ Extensible Mark-up Language XML)
to answer research questions addressing risk factors and disease natural history.
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Call Identifier: EOI.FP6.2002
As the result of the project partners will able to compare the results of different factors in sera with genetic
background, determine the factors are responsible for the disease and make recommendation for the best
therapeutic modality.
EXCELLENCE: The feasibility of putting together the critical mass of resources and
expertise needed to achieve the network's objectives and to be a world force on the research
activities proposed

2.1
Project Management
The co-ordinator of the project is Sandor G. Vari, MD Managing Director of VAREIMED Ltd., Hungary
has extensive experience in the co-ordination of large scale EU projects. At the same time he is familiar
with the USA system, since he was able to complete 11 Small Business Innovation Research Grants for the
National Institute of Health and for the Department of Defence. He is capable to create platform for
Integration of activities:
o
coordinated programming of the partners’ activities
o
sharing of research platforms/tools/facilities
o
staff mobility and exchanges
o
relocation of staff, teams and equipment
o
reinforced electronic communication networks
Activities to spread excellence
o
training of researchers and other key staff
o
dissemination and communication
o
networking activities to assist knowledge transfer
all within a unified management structure.
The subcontractor of VARIMED Ltd. is VITAMIB SARL. France will provide the IT support for the eForms,
and INFONET from Slovenia the web based shared medical record and for the project management using web
management tool: Project NetBoard.
2.2
Joint Research Activities
Scientific co-ordinator: Professor A. Salvador Peña Very extensive studies on associations of different
genetic factors and IBD, including genetic typing for IL-1B, TGFB, IL-1RA, HLA, TNFA, LTA, FAS,
NOD2/CARD15. Has existing collaborations with the Hungarian group. International director of IBD Unit,
Department of Gastroenterology, Hospital Clínico San Carlos, Madrid, Spain. He is capable to create
platform for
Joint research activities
o
a programme of joint research, possibly long-term
2.3
Dissemination and Communication
The European Federation of Crohn's and Ulcerative Colitis Associations (EFCCA) will have curtail role to
Activities to spread excellence
o
dissemination and communication
o
networking activities to assist knowledge transfer
Over the past decade, often with EFCCA support and advice, national self-help associations have been set up
in Eastern Europe with the result that as at the end of the year 2001. The EFCCA membership has risen to 19
European National IBD Patient Associations.
2.4
Long Term Joint Research
The Consortium composed from well-known expertise they studied different genetic factors and serological
disease markers of patients with Ulcerative Colitis and Crohn’s diseases. Partners all together from this field
published more then 200 peer review papers.
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Call Identifier: EOI.FP6.2002
2.4.1
Genetic Studies
Their genetic studies are including CARD15/NOD2 Mutational Analysis and Genotype-Phenotype
Correlation; refinement and physical mapping of a chromosome 16q candidate region; analyses of
chromosome 12 loci with Inflammatory Bowel Disease. Genetic studies on the associations between different
markers (a locus on chromosome 16q, NOD2 leucin rich repeat, thiopurin S-methyltransferase) and IBD.
Genetic regulation of some complement proteins (C4, Bf, C3, MBL), detection of -238 and -308 promoter
polymorphismsof the TNFalpha gene. Study of endogenous antibiotic genes (defensins) as critical mediators
of mucosal protection.
2.4.2
Serological Investigations
Experience with serological investigations (ANCA, ASCA) and pathogen intestinal flora (genetically
determined pathogen E. coli strains). Studies on the functional and therapeutic role of pro- and antiinflammmatory cytokines (TNFα, IL-6, IL-10, IL-12, IL-1b) and expression of adhesion molecules in
inflammatory bowel disease. Studies on the role of specialised epithelial cells, particularly Paneth cells, in
inflammatory bowel disease, and their influence on immune cell function, and interaction with pathogens and
resident microbial flora.
Deficiencies in humoral immune response against 60 kd bacterial heat shock proteins (hsp) was also studied
in IBD, study of epitope specificity and genetic regulation of anti-hsp antibodies. Measurement of
complement proteins, complement activation products and antibodies against complement proteins in the sera
of IBD patients and use of these measurements in differential diagnosis of Crohn's disease and ulcerative
colitis.
2.4.3
Role of pathogen intestinal flora
Others studied the role of pathogen intestinal flora in IBD. Studies on regulation of steroid receptor expression
in IBD. Partner will study the different changes of mucosal bacteria before and after treatment and according
to various degree of inflammation. Another important point is to analyze the relationship between luminal and
mucosal bacteria.
2.4.4
Surgery for IBD
The involved surgical groups have many years of experience in surgery for inflammatory bowel disease. They
are studying of molecular and genetic factors (genetic polymorphisms) that predispose to post-surgical
recurrence in Crohn’s disease, and the development of pouchitis after total restorative proctocolectomy in
ulcerative colitis. They are also investigating thrombotic risk factors (genetic and acquired)in inflammatory
bowel disease and having studies on the association between appendectomy and ulcerative colitis.
2.5
1
2
Core Group:
Organization
Country
Varimed Ltd.
Hungary
Infonet Kranj
Slovenia
Slovenia
Vitamib Sarl.
France
Department of
the
Gastroenterology and Netherlands
Head, Laboratory of
Immunogenetics,
Vrije Universiteit
Medical Centre,
Amsterdam
3
Chief
scientist
Dr. Sandor
G. Vari
Area of excellence
Management and
coordination of EU
projects, web based
electronic record,
eForms.
Bostjan
Web based shared
Bercic
medical record,
associated contractor
Xavier
eForms, electronic
Fabre
database
Professor A. Studies on associations
Salvador
of different genetic
Peña
factors
EoI IBDEXPERTNET Final
Role in the project
Creation of common platform for
IBD research via WEB based virtual
and interactive working methods
Project NetBoard, web based
electronic patient records, eForms for
genomic and proteomic protocols.
WEB based interactive education
tools for young scientist and for the
public.
Retrospective and prospective studies
of the existing cohort.
Genetic typing for IL-1B, TGFB, IL1RA, HLA, TNFA, LTA, FAS,
NOD2/CARD15
02/12/16
Call Identifier: EOI.FP6.2002
3
Division of
USA
Gastroenterology,
Department of
Medicine CedarsSinai Medical Center,
Los Angeles, CA
Cedars-Sinai Medical
Center, Department
of Medicine, Division
of Medical Genetics
Centres for
UK
Gastroenterology and
Hepatology, Royal
Free & University
College Medical
School
4
5 3rd Department of
Internal Medicine,
Semmelweis
University, Budapest
6
Hungary.
Medizinische Klinik Germany
und Poliklinik,
Abteilung
Gastroenterologie,
Universitatsklinikum
Charite, HumboldtUniversitat zu Berlin
Division of
Germany
Gastroenterology,
Robert Bosch Krhaus
And University of
Hohenheim, Stuttgart
Department of
Germany
Internal Medicine I
University of
Regensburg
93042 Regensburg
7
8
9
University Bologna,
Department of
Gastroenterology
4
Italy
Professor
Stephan
Targan
Studies on serological
disease markers of
patients with ulcerative
colitis and Crohn’s
diseases.
Dr. Jerome I Studies on different
Rotter and
genetic factors
co-workers
Professor
Humphrey J
Hodgson
and Dr
Satish
Keshav
Studies on the
functional and
therapeutic role of proand antiinflammmatory
cytokines and
expression of adhesion
molecules in
inflammatory bowel
disease.
Dr. Laszlo
Studies on serological
Bene, Prof. disease markers of
George Fust patients with ulcerative
Dr. Agota
colitis and Crohn’s
Kovacs
diseases
Dr. Zoltan
Prohaszka,
Dr Lilian
Varga
Professor
Main research interest
Herbert
in studying the role of
Lochs
cytokines.
Retrospective and prospective studies
of the existing cohort.
Genetic studies, serological
investigation, and study the role of
pathogen intestinal flora.
Transcriptional tissue profiling and
perform prospective clinical studies
of novel gene polymorphisms as they
relate to risk of IBD.
Retrospective and prospective studies
of the existing cohort.
Studies on the role of specialized
epithelial cells, particularly Paneth
cells, in inflammatory bowel disease,
and their influence on immune cell
function, and interaction with
pathogens and resident microbial
flora.
Retrospective and prospective studies
of the existing cohort.
Humoral immune response against
60 kd bacterial heat shock proteins
(hsp) in IBD, study of epitope
specificity and genetic regulation of
anti-hsp antibodies.
Retrospective and prospective studies
of the existing cohort. Studying the
role of cytokines (TNFα, IL-6, IL-10,
IL-12, IL-1b) in IBD, especially for
therapy monitoring and relapse
prediction. Studies on the role of
pathogen intestinal flora in IBD.
Professors
Strong experience with Retrospective and prospective studies
Eduard F.
therapeutical
of the existing cohort.
Stange and application of different Studies on intestinal defensins
C. Bode
drugs.
probiotics, cytokines and heat-shock
protein expression.
Professor
Core facility
Study the role of genetic
Dr. Jürgen „Molecular
polymorphisms for the pathogenesis
Schölmerich Immunologic markers of IBD in specific primary intestinal
Dr. Gerhard in IBD” in the German cell populations (macrophages,
Rogler
IBD-Competence
epithelial cells). Development of new
Network, data-banking, treatment strategies from the
serum-bank, datamolecular analysis of IBD-mucosa
management,
associated macrophages. Prospective
horizontal and vertical studies of the cohort within the
knowledge transfer
planned network Gene profiling in
isolated specific cell populations und
treatment conditions
Professor
Study the different
Retrospective and prospective studies
Massimo
changes of mucosal
of the existing cohort. Study the
Campieri
bacteria before and
different changes of mucosal bacteria
after treatment.
before and after treatment and
according to various degree of
inflammation. Analyze the
relationship between luminal and
EoI IBDEXPERTNET Final
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Call Identifier: EOI.FP6.2002
mucosal bacteria.
10 University Hospital
Heraklion,
Department of
Gastroenterology
Heraklion, Crete
11 Unidad de
Enfermedad
Inflamatoria
Intestinal, Servicio
Aparato Digestivo,
Hospital Clínico de
San Carlos Madrid
12 Servicio de Cirugía
General y Digestiva,
Instituto Catalán de
Oncología, Ciudad
Sanitaria y
Universitaria de
Bellvitge, Hospitalet
del Llobregat,
Barcelona
13 European Federation
of Crohn's and
Ulcerative Colitis
Associations
(EFCCA)Bearwood,
Bournemouth

3.1
Greece
Dr. Ioannis
Koutroubak
Experience with
serological markers of
IBD (pANCA, ASCA,
YKL-40, VAP-1,
Laminin).
Studies on serological
disease markers of
patients with IBD.
Studies on thrombotic risk factors
(genetic and acquired) in
inflammatory bowel disease. Studies
on the association between
appendectomy and ulcerative colitis.
Genetic studies, serological
investigation, and studies the role of
pathogen intestinal flora.
Spain
Dr. Julio
GarcíaParedes
Spain
Dr Javier de
Oca,
Dr Juan
Martí
Ragué,
Dr Gabriel
Capella
Many years of
experience in surgery
for inflammatory bowel
disease.
Study of molecular and genetic
factors (genetic polymorphisms)
that predispose to post-surgical
recurrence in Crohn’s disease and
the development of pouchitis after
total restorative proctocolectomy in
ulcerative colitis.
UK
Mr. Rod
Mitchell
Support and advice,
19 European National
self-help associations.
Dissemination and communication,
networking activities to assist
knowledge transfer to the public and
educate patients.
INTEGRATION AND STRUCTURING EFFECT: The means by which the Network of
Excellence will have a structuring and integrating effect on European research and assist in
spreading European scientific excellence
General outline of the joint programme of activities
Aim of the project to implement a Network of Excellence and via the network
select the best therapeutical modality for patients with IBD. The following studies
will be performed:
Integrate multicenter network into a Network of Excellence via IT tools
Implement web base tools (e-Forms and patient record) for database generation and management.
Genetic studies:
Gene for Crohn’s disease
NOD2/CARD15 in Chromosome 16
Polymorphisms,
Cytokine- Cytokine receptor
Glucocorticoid receptors
Defensins
Others
Study of
pathogen
intestinal flora:
E. coli
Clostridium
Others
Assessment of disease
activity markers:
Cytokine levels
Acute phase proteins
Complement activation
products
Others
Serological
measurements:
ANCA
ASCA
Heat-shock
protein –
antibodies
Others
Best therapeutic modalities for the patient
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3.1
Work packages
WP01 The operation of the IBDEXPERTNET (co-ordination and management activities)
Phase 1. Implementation of integrated network and utilization of information technology
tools (IT) for interactive working methods
WP02 Development of IBDEXPERTNET NetBoardthe for virtual and interactive working methods.
WP03 Integrate a multicenter network for performing retrospective and prospective studies in different
ethnic cohorts of IBD patients.
WP04 Integrated web site with the help of European Federation of Crohn's and Ulcerative Colitis
Associations EFCCA to provide up to date information on the new developments in diagnosis and
treatment of the IBD patients.
Phase 2. Retrospective and prospective studies to investigate the genetic origin of IBD
WP05 Inventory of proven genetic origin (IL-IRA,HLA) in families at high inherited risk for IBD.
WP06 Standardization of the genetic methods to be used for testing the samples collected in different
cohorts.
WP07 Development of new DNA chips for standard clinical diagnosis.
WP08 Establishment of an international database for the better understanding of IBD
WP09 Training of researches for the use of standardised methodology
Phase 3. Identification of factors responsible for IBD
WP10 Study of pathogen intestinal flora: E. coli Clostridium and others
WP11 Assessment of disease activity markers: cytokine levels, acute phase proteins, complement
activation products and others
WP13 Elucidate immunological parameters: screen in sera the complement factors, heat shock proteins
(HSP60-65, HSP70) , ANCA, ASCA etc.
Phase 4. Pilot study of different cohorts
WP14 Compare the results of different factors in sera with genetic background and determine the factors
are responsible for the disease make recommendation for the best therapeutic modality
WP15 Completion of a joint research infrastructure, adaptation of developed methodologies and
information technology use into the daily practice.
WP16 Spreading the excellence the developed methodologies, model experiments and results of research
activities developed during previous WPs.
WP17 Analysing the socio-scientific-economic impact of the research carried out by IBDEXPERTNET
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3.2
The operation of the network
The work packages (WPs) are the hubs for the step wise project implementation, and each WP will be
completed by a group of participants. In order to do so the Working Groups must organise itself as an
organisation, combining or integrating work and learning. To provide structural frame to achieve the goals of
the IBDEXPERTNET project the participants will form:
The Management Team (MGT) will provide any details in the accompanying administrative processes as
well as controversial issues in the network. The role of MGT to ensure that the project addresses innovation,
integration of projects results so that they can be integrated at a strategic project level, organisational level and
in a wider environment of partners. The project management daily base will take place on the Project
NetBoard.
The Development Team (DPT) addresses innovation to achieve the programme objectives. It will have a
role in the final arrangement of the research resources, medical and bioinformatic tools and will secure the
interoperability. Establishment of a dynamic strategic platform between the relevant actors in the field (the
participating research organisations, international medical societies, and interested industries) is a key issue.
Regularly it will be reviewed, evaluated and modified on the Project NetBoard.
The Validation Team (VLT) will report the results of verification stages. The role of VLT to ensure that
the developed genetic methods, serological measurements and methods for the assesment of disease activities
are suitable for the assigned clinical applications and evaluates new and improved prototypes/ processes/
services in the networks.
The CO-ORDINATOR makes the final consensus decisions concerning all aspects (scientific, management,
electronic communication, and networking). They also dealing with inter-operability; design of exploitation
scenarios; concertation with the participating research institutes and service providers; involvement of
sponsors should the case happen; trouble shouting; dissemination and exhibition of the Project achievements;
up-date of success indicators; preparation of deployment and cost analysis.
Co-operation between the partners is promoted through regular meetings of the MANAGEMENT BOARD
every 3 months (more frequently during the first 6 months of the project). Every six months a mandatory self
evaluation will take place, where the partners will review the deadlines and the progress of the project. The
meetings are organised by the board members, one after the other, and will provide the opportunity to visit the
places where significant work is done. Meeting cost is shared among attendants and incurred on their
respective project budgets. Meeting dates and agenda are fixed in advance and, at the latest, from one meeting
to the next.
3.3
The plan for the dissemination
The medical participants in IBDEXPERTNET are participating in international medical societies, in which
they often play a leading role, and are contributing to international works such as the European Federation of
Crohn’s and Ulcerative Colitis Associations (EFCCA) an “umbrella” organization of 19 National Member
IBD Patient Associations.
The partners will exploit a mix of resources between standard tools for dissemination and communication
solutions. The use of Internet and web tools will be one of the keys of this activity.
The communication and dissemination plan will consists in:
 Public information on the research activities on the IBDEXPERTNET portal. (links with others web
sites);
 Specific communication policy-plans for specific users: members of the consortium, patients, general
practitioners (GPs), etc.;
 Participation with presentation of the project activity to a number of conferences or other similar events
addressed (social events etc.);
 Publications on specialised pee review papers;
 Preparation and distribution of brochures concerning project’s results.
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