Training
General. The network as a whole undertakes to provide a minimum of 480 person-months of
Early Stage (ESR) and Experienced Researchers (ER) whose appointment is financed by
European Community.
More specifically, it is foreseen to deliver 288 person/months of ESR and 192 person/months of ER training.
The ultimate objective of the project is to train the ESR and ER such that they will be able to compete
succesvully for respectively 'postdoc' and tenured positions in the EU-member states and thus contribute
significantly to the strenghtening of EU-based research. For this purpose an individual career development
plan will be drafted for each trainee. At the start of their contract, the trainees will be informed on the
research training opportunities within the network by their supervisor. The supervisor and trainee will
together draft the most favorable plan for the trainee. The supervisor will be responsible for monitoring,
the progress of the execution of the career development plan.
Training of ER. The network will enable ER with different background (e.g. molecular biology,
immunology) to participate in a multidisciplinary setting where they will not only be exposed to a state
of the art scientific environment, but will also have the opportunity to develop management and
organisatorial skills. In the first year the ER will participate in the ongoing research of the
group in which they are employed, studying disease model(s) and immune deficient mice already present
in the laboratory. Ideally the trainees will contribute to the ongoing research program their individual
expertise while at the same time being exposed to complementary sciences. We intend to execute
the program at the highest possible level and therefore will recruit talented ER giving them
the opportunity to implement their monodisciplinary expertise in the biomedical field. The ER will
have regular contact with each other via e-mail and the IMDEMI Website and the supervisors of the
platforms and will be heavily involved in the scientific management of the project. In all except
one laboratory the employment of the ER will start either a year before (with one year overlap) or
at the same time as the employment of the ESR. Therefore the ERs will provide top quality expertise
for the ESRs within the different research groups.
Training of ESR. From the beginning the ESR will get support from the ER. In addition the IMDEMI
website will provide a direct discussion forum for ESR and ER for the large variety of technical and
scientific issues relevant for the project. On one hand the ESRs will be trained in mouse molecular
genetics by participating in the generation of the mouse models in collaboration with and with strong
support from the central mouse platform. On the other hand the ESRs will be trained in fundamental
immunology by participating in the in vivo analysis of the different genetically modified mouse models
mainly performed within the research groups they are employed. This will guarantee exposure of the early
stage trainees to different technologies and topics of research within the program, not only through the
projected annual meetings but also by enabling them to participate in different areas of research within
the project taking advantage of the availability of a large variety of expertise and implemented technology
within the participating institutes.
The Network wide Rotary training and research system. Each trainee will spend at least two working
visits in one of the other participants' labs as part of their training and even more if required for the
optimal execution of the project. ESR will be encouraged to execute parts of their research in groups other
than their respective host institute. Topics such as embryonic stem cell culturing and gene targeting by
homologous recombination, complex BAC engineering, controlling a bacterial infection model, cellular
immunology techniques, serological and/or histological analysis of specific organ damage, use of
micro-satellites for genotyping, particular phenotypic analyses, basic and advanced mouse breeding
strategies, determining efficiencies of Cre- mediated deletions in selected cell populations are
idealy suited to be trained and performed during short-term (2-6 months) visits of individual ESR and ER
at one of the participating laboratories mentioned.
Network wide central training and education activities. We will organize annual meetings for all
participants to be hosted by one of the participant's institutes.
- During these meetings the trainees will present their scientific results and progress towards the
objectives of the program.
- Special seminars will be organized to provide a free flow of information to others in the participating
institutes.
- The supervisors and their colleagues within the respective host institutes will provide expert seminars
during the annual meetings.
- Further, we will invite eminent scientists active in immunology research for specialized tutorials to be
held at our annual meetings.
- During these annual meetings workhops and courses (2-3 days) will be organized on specific topics. The projected subjects are:
- New developments in the technology of genetic modification of mice.
A joined meeting with the Annual workshop on Innovative Mouse Models, June 16-17,
2005 in Leiden, The Netherlands with the invited speakers Andras Nagy (Toronto), Christopher Contag (Stanford)
and Allan Bradley (Cambridge). Workshop website:
http://workshop.nki.nl
- Genotyping of genetically modified mice. Joined meeting with the
International Meeting 'Biology of the Immune defence' organised in the GBF Institute in Braunschweig,
Germany (Werner Müller) on Tuesday November 1, 2005. Invited speakers come from all over Europe and
from Israel.
- Mouse models for immunological diseases,
organized by Ari Waisman at the Clinic of the Medical School of the University
of Mainz, May 26, 2006.
- Cellular Immunology course. Organized by Oxford University (Fiona Powrie)
in
March 20-22, 2007.
- 4th Workshop on Innovative Mouse Models, June
21-22, 2007 in Leiden, The Netherlands. Keynote speakers: Neal Copeland,
Wolfgang Wurst, Jost Seibler. Workshop website:
http://workshop.nki.nl
- Visit to the
large pharmaceutic company Hoffmann-La Roche, Basel, 28 May 2008. Organized by
Sjef Verbeek for all research fellows.
- 'Frontiers
in allergy and autoimmunity', organized by Ari Waisman at the Clinic of the
Medical School of the University of Mainz, 30 –31 May 2008.
-
Workshop on Mouse models for functional genomics in
immunology, organized by Werner Müller in Braunschweig, 23 September 2008.
-
Immune deficient animals: Mouse models of
immunological diseases, organized by Sjef Verbeek and Ari Waisman with keynote
speaker Jeffrey Ravetch. Hosted by IMBA, Vienna on 11-12 May 2009.
- Ethical issues related to the project .
Local training (overview
of local PhD programs). The early stage trainees will be enabled to participate in the
masters/Ph.D.
programs existing in the respective research institutes.
- All participating academic institutes provide special courses to improve
writing, presentation, management
skills and to optimize career development. Since we consider these aspects essential for researchers we will
strongly encourage the trainees to participate in such courses as required depending on the previous e
ducation of the trainees.
- The individual appointed scientists will be allocated to one of the participating institutes where
she/he
will receive the individual training connected to the execution of the project. Due to the involvement of
multiple partners in most tasks all scientists will receive additional training in areas of research related
but distinct to their own work. We estimate that the ratio between the individual and network-wide training
will be 70:30.
Phenotypic analysis of previously generated genetically modified mouse models already present within the
laboratories of the different participants of the network and studies with disease models directly related
to the new genetically modified mice that will be generated will be initiated directly from the
beginning:
1. LUMC, Sjef Verbeek en Moh Daha: Analysis of the phenotype of constitutive FcgRI and FcgRIII and
conditional FcgRII KO mice in a large variety of functional assays and disease model. Establishment of
mouse models of glomerulonephritis (anti-GBM nephritis) and tubulo-interstitial inflammation
(unilateral
urether obstruction, renal transplantation). PhD
program and courses
2. JGUM, Ari Waisman: Analysis of genetically modified mice with defined impaired B cell function in
bacterial infections and in disease models, e.g. EAE, SLE and diabetes. PhD
program and courses
3. Imperial, Marina Botto: Assessment of renal pathology in mice deficient in factor H or in other complement
component already available in the host laboratory. Establishment of new models of experimental
glomerulonephritis and/or tubular injury. PhD
program and courses
4. HZI (former GBF), Werner Müller: Exploiting the already generated conditional IL-10 and conditional IL-10 receptor
mutant mice within the disease models provided in the network like Helicobacter infection (Fiona
Powrie),
EAE (Ari Waisman) and arthritis (Jürgen Roes). PhD
program and courses
5. UniK, Manolis Pasparakis: Establishment of mouse models of inflammatory bowel disease (IL-10 knockout
mice, dextran sulfate induced colitis), EAE and atherosclerosis (ApoE-/- mice). PhD
program and courses
6. UCL, Jürgen Roes: Role of myeloid cells and their effector mechanisms in arthritis and
EAE. Role
of TGF-b mediated homeostasis in the prevention of arthritis and EAE. PhD
program and courses
7. UniOx, Fiona Powrie: Immune regulation in the intestine. Continued in vivo analyses of the roles of
CD4+ T cells and cytokines in exacerbation or suppression of bacterially triggered intestinal
inflammation.
Incorporation of the conditional IL-10 and IL-10R KO mice that are already available into these studies.
PhD
program and courses
8. IMBA, Josef Penninger: Control of immunotolerance and T cell
activation. Continued biochemical and
genetic analysis of cbl-b, card11, and adap null mice. PhD
program and courses
Research
The project is based on one main technology platform, the central mouse platform, that serves as a centre
for the generation of the mouse models, surrounded by eight research groups
focusing on the phenotypic analysis and application of the newly generated genetically modified mice in human disease models. The following four laboratories form together
the mouse technology platform:
- Werner Müller, Helmholtzzentrum (former GBF), Braunschweig, Gerrmany
- Josef Penninger, IMBA GmbH, Vienna, Austria
- Manolis Pasparakis, University of Cologne, Germany
- Sjef Verbeek, LUMC, Leiden, The Netherlands
Collaboration and exchange of tools and materials between these four centres guarantees an effective use
of all resources. Leiden Genome Technology Center (LGTC) and GBF provide mouse BAC and YAC libraries for
the construction of the different targeting vectors.
All appointed researchers are involved in the generation of a particular genetically modified mouse model
on the basis of the research objectives and priorities of the participating research group in which they
are employed. The whole process from DNA to mouse is conducted by the group leaders of the laboratories of
the mouse platform.
A soon as a newly generated genetically modified mouse model becomes available a basic analysis of the
phenotype will be performed designed for that particular genotype and a suitable breeding program initiated
e.g. breeding with Cre expressing mice other (genetically modified) mouse strains etc. Upon phenotypic
characterization the mice will a used in as many as possible disease models established in the laboratories
of the participants.
Taken together two main tasks will be executed in the project:
- Generation of new mouse models
- Phenotypic analysis and application in disease models of the newly generated mouse strains
After completing the construction of the required targeting vectors/ transgene constructs, - the initial
step in generating new mice - the actual gene targeting as well as the final generation of the transgenic
and KO mice will be performed in the embryonic stem cell- and embryo manipulation facilities within the
four mouse centres.
Subsequently the appointed researchers do not only use the newly generated models within their own research
but provide the mice also to all other participants of the network for other specific research objectives.
The appointed researchers will intensively collaborate with other participants and participating institutes
to optimally utilize the broad variety of techniques for the phenotypic analyses of the immune system of the
mouse present within the network together with many different mouse models of (human) immunological diseases.
The analysis of the phenotype and the application in disease models is conducted by the leader of each
participating group.
With the newly generated mouse models a breeding program will be conducted and established.
All generated mouse strains will be subject of a central breeding and cryo-preservation program of the
SPF facilities of the mouse platform. For the generation of cell lineage specific KO mice the mice with
floxed target genes have to be crossed with the appropriate cell type specific Cre transgenic mice.
For some disease models back crossing of the KO on a susceptible strain is required (e.g. LDL receptor
KO for atherosclerosis). Because of redundancy double KO are sometimes required to analyse the biological
role of a particular gene. In conclusion, an extensive carefully controlled breeding program is a
prerequisite for a successful research program with genetically modified mouse models.
Ethical issues
Genetically modified mice are the basis of the proposed research in the IMDEMI RTN. And therefore ethical
issues are associated with the project. All participants agree with the European Commission that reviewing
ethical issues will serve two important functions, first to ensure that the EU can be confident that it is
not funding any research that is ethically unsound and secondly to continually raise awareness amongst
researchers of ethical issues that may be raised by their research and enable them to adequately address these. Within IMDEMI all research activities will respect fundamental ethical principles and will include national legislation, relevant EU legislation and standards, international conventions and declarations, opinion of the European Group on Ethics and Protection of Animals (e.g. 99/167/EC: Council Decision of 25/1/99 and EC Directive 86/609). National and local Committees that pay notice to the 3R's, (Refinement, Reduction and Replacement) and that judge all ethical aspects of the intended experiments, will have to give their explicit approval before any experiment will start.
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