WP2 - The animal model platform for chronic inflammatory diseases

WP coordinator: Rikard Holmdahl, Karolinska Institutet

We will establish a mouse and rat genetic platform integrated in the consortium and establish a functional network of pathway analyses between the interacting groups. This will require resources for one animal facility manager who will coordinate work between the different animal facilities. A database needs to be upgraded and maintained for embryo banks of different animal strains Resources will also be used for further studies of genetics and of pathophysiology of the model diseases in order to enhance their comparability with the human disease counterparts. One junior scientist will be employed for this work.

This platform will establish a center for use of animal models for CID. This will require an animal model platform, which is genetically and pathogenically controlled. The animals need to be standardized to be useful and comparable for use in the different groups. Genetically the mouse models will be on the C57Black background and the rats on the DA background. They should be pathogen free in accordance with FELASA standard and should optimally be kept as frozen embryos. We will have an added resource to make selected strains germfree. All conserved animals should be >10k SNP typed so that there are full genetic control.
A strict genetic standard with C57Bl/10 and C57Bl/6J will be established. The C57Black is chosen since the C57Black is likely to be the most common genetic background to be used internationally. It is not defined however since B6/B10 substrains differ considerably between different colonies and in particular do the B6 used as ES cell differ from B6/J. The best available C57Bl for inflammation models is the B10.Q and the most intenationally standardized C57Black strain is B6J, both have well defined C57Black backgrounds. The B10.Q is in particular already available with both congenics fragments and relevant genetic modifications already inserted. This is >10k SNP typed and bred sister brother in a controlled colony. We will also produce a B10Q with a congenic fragment which makes the easy to breed and to conserve. In a separate nucleus breeding we will also have B6J. Introgressing genes or chromosomal fragments from other C57Bl strains to the B10Q or the B6J will be relatively easy as the linked genes are likely to be shared.
For the DA the strict genetic standard will be DA.Harlan. All DA substrain has been genotyped and there are some significant differences of clear impact of CID that can be corrected through backcrossing. The DA-Harlan is maintained as a nuclei with strict brother-sister mating. Breeding of nuclei animals will be performed at any unit that fulfils the standard but the center unit will be Scheele animal house at MBB, KI. If there are available space the rat nuclei could be bred at CMM animal unit if conditions can be fulfilled. For freezing and conserving mice we will use the KI transgenic unit and will establish a link with EMMA. For establishing germfree mouse and rat strains we will use the germfree unit at KI. Cesarian sections can be made locally but for embryo-conservation of rats we will use the EURATOOLS Prague unit. Optionally the standards strains will be maintained in the KI germfree unit. Based on the standard strains a series of congenic and genetically modified strains, of importance for CID studies, will be maintained and continually established. Particular emphasis will be made to establish strains to address molecular pathways revealed by the genetic analysis of human CID.
Using the defined strains we will establish useful models at the different participant COMBINE units for rheumatoid arthritis, multiple sclerosis, psoriasis, cardiovascular disease, type I diabetes, systemic lupus erythematosus, inflammatory bowel disease, relapsing polychondritis, asthma bronchialis, and contact dermatitis.
The data on animal model testing, genetic selection as well as genetic experiments for all used animal species should be give a possibility to be inserted in a database supported by WP3.


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