Role of atypical Protein Kinase C in Inflammatory Bowel Disease

描述（由申请方提供）：炎症性肠病被认为是由遗传易感宿主对肠道微生物的不适当免疫应答引起的。先天免疫系统对微生物的异常感知触发了致病性T淋巴细胞的发展，这些T淋巴细胞引发并传播肠道炎症。最近的证据表明，一种称为不对称细胞分裂的进化保守机制在调节对微生物的适应性免疫反应中发挥了新的作用。在不对称分裂过程中，细胞命运决定因子向分裂平面一侧的分离使它们能够不平等地遗传和子细胞命运的分歧。我们以前已经表明，T淋巴细胞似乎经历不对称分裂，产生两个不同命运的子细胞（J.T. Chang等人，Science 2007）。此外，我们观察到，在其他模式生物中调节极性和不对称分裂的保守的非典型PKC（aPKC）-Par 3-Par 6和Scrib-Dlg-Lgl极性复合物在招募到针对微生物病原体的免疫应答中的分裂T细胞内建立互补结构域。 我们实验室使用过继转移结肠炎模型的初步证据表明，CD 4 + T细胞可能在对肠道微生物的免疫应答失调期间发生不对称分裂。我们假设极性网络调节活化的CD 4 + T细胞的不对称分裂，影响其分化为致病性结肠炎诱导细胞。在这项提案中，我们将测试的假设，aPKC和Scrib极性复合物调节的能力，CD 4 + T淋巴细胞进行不对称分裂，分化为致病性Th 1和Th 17效应细胞，并介导肠道炎症。这些目标的实现可能会对IBD发病机制的基本机制产生重要的见解，并可能确定未来治疗可能针对的新靶点。

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.