MAPPING SUSCEPTIBILITY GENES IN MURINE COLITIS

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Pathogenesis if inflammatory bowel disease (IBD) in humans is multi- factorial, involving complex interactions among genetic, environmental, and immunological factors. Genetic disruption of the Interleukin-10 ((Il10) gene in mice predisposes to spontaneous development of IBD. However, the severity and extent of the IBD syndrome is controlled by as yet unidentified genetic background modifiers. A severe juvenile-onset colitis in cecum, proximal, middle, and distal colon is elicited by IL-10 deficiency in C3H mice by 4 weeks of age, whereas the B6-IL10-/- have developed little or no lesions by 12 weeks of age. Project 4 of this Program Project grant proposes to use quantitative trait locus (QTL) mapping techniques to identify the genetic basis for these differential strain susceptibilities, and to use this information to indicate relevant phenotypes and thus, candidate genes, for testing in IBD-susceptible humans. The validity of this approach was demonstrated during the previous support in which 6 chromosomal regions were identified that contained genes controlling differential strain susceptibility to experimental colitis induced by dextran sulfate sodium. The specific aims of the project are (1) to use genetic segregation analyses to establish the chromosomal locations of colitis susceptibility loci that confer significantly more severe colitis in C3H/HeJBir.IL10-/- mice and (2) to validate phenotypic effects of colitis loci by producing interval-specific congenic stocks of C3H mice carrying putative resistance alleles from B6, and reciprocally, B6 stocks carrying putative susceptibility alleles from C3H. This approaches should allow fine mapping and candidate gene testing for IBD-predisposing background genes required to interact deleteriously with an inadequately suppressed effector population. Delineation of the genetic mechanisms predisposing to IBD in these mouse models will suggest likely pathways for therapeutic intervention in humans and possibly even allow identification of homologous human genes.