Structure function studies in intestinal epithelial JAM

描述（由申请人提供）：本提案的中心主题是基于不断发展的概念，即紧密连接（TJ）蛋白不只是作为静态的物理屏障形成元件，而是作为调节肠上皮细胞内关键稳态功能的信号中心。这一概念与在溃疡性结肠炎和克罗恩病等与肠道内稳态失调相关的人类疾病中的发现一致，其中TJ蛋白表达的改变与肠上皮屏障功能缺陷和广泛的粘膜溃疡/损伤有关。本提案的目标集中在阐明紧密连接蛋白JAM-A信号如何控制上皮屏障和细胞迁移的基本机制。它将特别关注识别与JAM-A相关的新的近端信号元件，这些元件在连接组装和稳定状态期间调节屏障（Aim 1）。它还将重点阐明JAM-A如何通过在蛋白质运输和小分子水平上对β 1整合素动力学的影响来调节细胞迁移

DESCRIPTION (provided by applicant): A central theme of this proposal is based on the evolving concept that tight junction (TJ) proteins do not function simply as static, physical barrir forming elements but as signaling centers that regulate critical homeostatic functions within intestinal epithelial cells. This concept is consistent with findings in humans that have condition associated with dysregulated intestinal homeostasis such as ulcerative colitis and Crohn's Disease where altered TJ protein expression is associated with defective intestinal epithelial barrier function and extensive mucosal ulceration/wounding. The goal of this proposal is centered on elucidating fundamental mechanisms of how the tight junction protein JAM-A signals to control epithelial barrier and cell migration. It will specifically focus on identifyingnovel proximal signaling elements linked to JAM-A that regulate barrier during junctional assembly and during the steady state (Aim 1). It will also focus on elucidating how JAM-A regulates cell migration through effects on beta 1 integrin dynamics at the level of protein trafficking and small GTPase signaling. We have demonstrated that JAM-A mediated regulation of cell migration and barrier are dependent on dimerization of JAM-A in a cis configuration within the same cell. In aim 3 of this proposal, we will extend these important findings to determine the role of dimerization of JAM-A between cells in trans and if such interactions play a role in regulating cell migration and barrier. Knowledge gained from these studies will not only shed new light into mechanisms of outside-in signaling at the TJ that regulate permeability, migration and proliferation, but may also provide new ideas for therapeutic targets with diverse applications ranging from enhanced vaccine/drug delivery to wound healing/anti-inflammation or inhibition of cancer progression.