Role of atypical Protein Kinase C in Inflammatory Bowel Disease

描述(申请人提供)：炎症性肠病被认为是由于遗传易感宿主对共生肠道微生物的不适当免疫反应所致。先天性免疫系统对微生物的异常感知触发了致病T淋巴细胞的发展，这些T淋巴细胞发起和传播肠道炎症。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。在不对称分裂中，细胞命运决定因素被分离到分裂平面的一侧，导致它们的不平等遗传和子细胞命运的分化。我们之前已经证明，T淋巴细胞似乎经历了不对称分裂，从而产生了两个不同命运的子细胞(J.T.Chang等人，科学，2007)。此外，我们观察到，保守的非典型PKC(APKC)-Par3-Par6和Scrib-DLG-LGL极性复合体，在其他模式生物中调节极性和不对称分裂，在分裂T细胞内建立互补结构域，被招募到对微生物病原体的免疫反应中。我们实验室使用结肠炎过继转移模型的初步证据表明，在对共生肠道微生物的免疫反应失调期间，CD4+T细胞可能经历了不对称分裂。我们假设，极性网络调节激活的CD4+T细胞的不对称分裂，影响它们分化为致病的、诱发结肠炎的细胞。在这项研究中，我们将验证以下假设：aPKC和Scrib极性复合体调节CD4+T淋巴细胞进行不对称分裂，分化为致病的Th1和Th17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.