Role of Polarity Complex Signaling on Non-muscle Myosin in Intestinal Epithelia

描述（由申请人提供）：我们的实验室最近报道了“极性复合物”（非典型PKC-Par 3-Par 6），一种进化上保守的信号传导途径，在炎性TNF信号传导下被深度下调。它在结肠炎小鼠模型以及溃疡性结肠炎和克罗恩病患者中也下调。 由于炎症性肠病代表了人类健康的一个重大问题，我想进一步分析aPKC下调的下游后果。我们发表的和初步的数据表明，极性复合物对非肌肉肌球蛋白IIA的激活施加拮抗控制，肌球蛋白IIA是上皮细胞中广泛接受的炎症信号传导效应子。其他实验室已经表明nmMyosin II参与紧密连接 维持和下游的炎症信号，但我们是第一个假定具体的一个亚型nmMyoIIA作为主要的分子机制控制上皮屏障。因此，在这里，我提出的假设是：炎症依赖性下调的极性复合物aPKC是一种新的信号传导机制，协同上调顶端表达nmMyosinIIA废除直接磷酸化的重链。本研究旨在分析aPKC-Par 3-Par 6拮抗MLCK介导的nmMyosin II激活的作用及其分子机制。

DESCRIPTION (provided by applicant): Our laboratory recently reported that the "polarity complex" (atypical PKC-Par3-Par6), an evolutionarily conserved signaling pathway is deeply downregulated under inflammatory TNF signaling. It is also downregulated in a mouse model of colitis as well as in ulcerative colitis and Crohn's disease patients. Because Inflammatory Bowel Disease represents a substantial problem for human health, I would like to further analyze the downstream consequences of aPKC downregulation. Our published and preliminary data show that the polarity complex exerts antagonistic control on the activation of non-muscle Myosin IIA, a broadly accepted effector of inflammatory signaling in epithelial cells. Other laboratories have shown the involvement of nmMyosin II in tight junction maintenance and downstream of inflammatory signaling, but we are the first to postulate specifically one of the isoforms nmMyoIIA as the main molecular mechanism controlling epithelial barrier. Accordingly, here I put forth the hypothesis that: Inflammation-dependent downregulation of the polarity complex aPKC is a novel signaling mechanism that synergistically upregulates the apical expression of nmMyosinIIA abrogating direct phosphorylation of the heavy chains. This project is devoted to analyze the effects and the molecular mechanisms by which aPKC-Par3-Par6 antagonizes MLCK- mediated nmMyosin II activation.