WP 8. Identification of new targets for therapy using experimental rodent models for arthritis

This area of work will be lead by Partner 11 (Lund) with input from Partner 1 (KI), Partner 4 Vienna) Partner 8 (Nijmegen) , Partner 21 (EULAR) and Partner 24 (Biovitrum)

We have available animal model platform suitable for identifying the relevant genes for inflammatory autoimmune diseases. It is based on the identification of the major loci controlling development of well-defined mouse and rat models of RA. All these loci have been isolated in so called congenic strains, which require years of selective breeding but which are extremely useful for the next step in the analysis. All the congenic fragments have been placed in the mouse C57/Black genetic background for which genomic sequence and ES cells are available and for rat loci in the DA rat genetic background. In both rats and mouse models advanced intercross lines are available that provide more recombinations and a faster way to identify interacting disease haplotypes. In addition we have selected and made several new transgenics, mutations, knockouts and knock-ins that are all bred into the same genetic background. This gives us an advantage in the analysis of the pathways caused by the identified genes.

The strategy to isolate the genes will be based on selective recombinational selection in congenic strains using a strategy we already have successfully demonstrated that we can positionally clone genes in QTL (so far we have published the Ncf1 and the Aq genes and there are several genes in progress, Lorentzen). The most important loci have been isolated in well defined congenic strains. We now have 15 different mouse strains and 10 different rat strains and we will now aim to positionally clone the genes in these loci through 1) minimising the congenic fragment in selected congenics; 2) developing and analysing genetic interactions in partial advanced intercrosses; 3) analysing expression pattern of all genes within the selected congenics; 4) identifying the responsible polymorphism by sequence analysis; 5) reproducing the genetic polymorphism using ES cell and lentivirus based technology; and 6) analysing the functional pathway controlled by the cloned genes and transferring these results to collaborators within the consortium to study their role in MS and for target validation together with selected European SMEs.