SAMP1/YitFc (SAMP) mice develop a Crohn's-like ileitis, characterized by discontinuous inflammatory foci with associated epithelial changes. During the initial funding cycle of this program, we identified 4 susceptibility loci for this complex trait (lbdq1-4) through outcross to C57BL6 and AKR mice. These loci have been confirmed using interval-specific congenic strains, and we successfully identified an excellent candidate gene for the Ibdq2 locus, Ppar-gamma. We have also demonstrated a potential role for PPARG in human Crohn's disease by genetic association. In this application, we propose to use the established congenic strains 1) to identify the mechanism by which allelic differences in the Pparg gene control disease development in SAMP mice and 2) to define and characterize the role of specific candidate genes for each of the remaining susceptibility loci.
In Aim 1, we will identify the transcription factors required for tissue-specific expression of Pparg in the epithelial crypts of the small intestine, test the role of Ppar-gamma in modulating the epithelial response to inflammation, and determine whether differences in expression limited to the epithelial crypts can result in differential susceptibility to ileitis in SAMP and AKR mice.
In Aims 2 and 3, we will use the existing congenic strains or mice from new, highly informative crosses to further localize and identify the genes responsible for mapping to Ibdq1 (Chr 9), Ibdq3 (Chr 8), and Ibdq4 (Chr X) by recombinational methods. Finally, in Aim 4, we will define the role of epistatic modifiers of Pparg (Ibdq2) in modulating disease susceptibility. Taken together, these experiments will provide insight into the mechanisms of disease in this model as well as candidate genes for testing in human inflammatory bowel disease.
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