Role of atypical Protein Kinase C in Inflammatory Bowel Disease

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DESCRIPTION (provided by applicant): Inflammatory bowel disease is believed to result from an inappropriate immune response to commensal intestinal microbes in a genetically susceptible host. Aberrant sensing of microbes by the innate immune system triggers the development of pathogenic T lymphocytes that initiate and propagate intestinal inflammation. Recent evidence has suggested a novel role for an evolutionarily conserved mechanism called asymmetric cell division in regulating adaptive immune responses to microbes. During asymmetric division, segregation of cell fate determinants to one side of the plane of division enables their unequal inheritance and the divergence of daughter cell fates. We have previously shown that a T lymphocyte appears to undergo asymmetric division to give rise to two differentially fated daughter cells (J.T. Chang et al., Science 2007). We observed, moreover, that the conserved atypical PKC (aPKC)-Par3-Par6 and Scrib-Dlg-Lgl polarity complexes, which regulate polarity and asymmetric division in other model organisms, establish complementary domains within dividing T cells recruited into an immune response against a microbial pathogen. Preliminary evidence from our laboratory using an adoptive transfer model of colitis suggests that CD4+ T cells may undergo asymmetric division during a dysregulated immune response to commensal intestinal microbes. We hypothesize that the polarity network regulates asymmetric division in activated CD4+ T cells, influencing their differentiation into pathogenic, colitis-inducing cells. In this proposal, we will test the hypothesis that the aPKC and Scrib polarity complexes regulate the ability of CD4+ T lymphocytes to undergo asymmetric division, differentiate into pathogenic Th1 and Th17 effector cells, and mediate intestinal inflammation. Accomplishment of these aims is likely to yield important insights about fundamental mechanisms underlying the pathogenesis of IBD, and could identify new targets against which future therapies might be directed.