Susceptibility to inflammatory bowel diseases (IBD) in human populations appears to have a significant heritable component. Modeling based on relative genetic risk data from family and population studies predicts that such susceptibility is multi-genic and that disease expression is influenced significantly by environmental factors which are, as yet, undefined. In the absence of a mechanism for identifying candidate genes, genetic studies in humans are unlikely to be successful because of the size of the study populations required for successful random linkage analysis and the inability to control for environmental influences on disease expression. Such problems are limiting factors which cannot readily be solved using the resources available. An alternative approach to studying the genetic control of susceptibility to IBD makes use of rodent models. These models have the distinct advantages of short generation times, potential for controlled breeding, and standardization of environmental influences. As outlined in the overview for this program, the SAMP1/Yit mouse strain provides a unique resource for studying genetic contributions to disease susceptibility in a spontaneous model of ileitis. In contrast to the other rodent models of IBD, this inbred mouse strain develops destructive inflammation of the distal small bowel with many of the pathological and histological features of Crohn's disease (CD). Penetrance is extremely high (100% by 30 weeks of age), and we have shown that disease expression can be largely inhibited by outcross to C57BL/6 mice, demonstrating the genetic control of the disease process in these mice. In order to begin to identify the specific genes involved in the IBD of SAMP1/Yit mice, we propose the following specific aims: 1. To define the model of inheritance of spontaneous ileitis in SAMP1/Yit mice by outcross and backcross breeding with relevant inbred mouse strains. 2. To localize the genes required for disease expression by genome-wide scans of F2 and backcross progeny from these crosses using microsatellite genotyping. 3. To develop disease-resistant recombinant congenic mice using a """"""""marker-assisted"""""""" selection strategy for functional characterization of ileitis susceptibility loci and the identification of interval-specific candidate genes.
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