Role of the chloride channel ClC-2 in intestinal tight junction barrier recovery

描述（由申请方提供）：肠上皮内位于顶端的细胞间紧密连接（TJ）作为细胞旁屏障，防止有害管腔抗原渗透。TJ屏障功能的丧失是肠道疾病和炎症性肠病的关键病理因素。新出现的证据表明，细胞内囊泡膜运输，包括小窝运输是形成紧密连接结构域的关键过程。 我们的初步研究表明，在上皮损伤的情况下，肠屏障的恢复在ClC-2氯离子通道蛋白的情况下受损。我们的初步研究还表明，ClC-2通过与小窝的相互作用调节关键紧密连接蛋白occludin的细胞内运输，在肠屏障恢复中起着至关重要的作用。 基于初步研究，我们推测ClC-2通过小窝蛋白-1依赖的过程促进紧密连接蛋白occludin的募集，在肠粘膜修复过程中起着不可或缺的作用。在具体目标1中，我们计划阐明ClC-2在封闭蛋白的小窝运输中的作用，并且在目标2中，我们打算确定ClC-2介导的肠上皮TJ屏障增强的机制。具体目标3致力于在体内测试我们的假设并定义ClC-2在肠屏障恢复中的作用。在临床上，肠粘膜屏障的修复是防止肠粘膜进一步损伤和治疗成功的必要条件。这项研究将为ClC-2在肠道屏障恢复中的关键作用提供新的见解。拟议的研究将为我们提供关于氯通道ClC-2如何增强肠道屏障功能的机制和潜在的治疗信息。

DESCRIPTION (provided by applicant): The apically located inter-cellular tight junctions (TJ) within the intestinal epithelium act as a paracellular barrier and prevent permeation of noxious luminal antigens. Loss of TJ barrier function is a key pathologic factor in intestinal disorders an inflammatory bowel diseases. Emerging evidence shows that intracellular vesicular membrane transport including caveolar transport is a key process in the formation of tight junction domains. Our preliminary studies indicated that the intestinal barrier recovery in the event of epithelial injury is impaired in the absence of ClC-2 chloride channel protein. Our preliminary studies also suggested that ClC-2 plays a vital role in the intestinal barrier recovery by modulation of intracellular trafficking of key tight junction protein occludin via its interaction with caveolae. Based on preliminary studies, we hypothesize that ClC-2 plays an integral role in the intestinal mucosal repair process by promoting recruitment of tight junction protein occludin via caveolin-1 dependent process. In specific aim 1, we plan to elucidate the role of ClC-2 in caveolar trafficking of occludin, and in aim 2, we intend to define the mechanisms of ClC-2 mediated enhancement of intestinal epithelial TJ barrier. Specific aim 3 is dedicated to testing our hypothesis in-vivo and defining the role of ClC-2 in intestinal barrier recovery. Clinically, repai of mucosal barrier in intestine is imperative for preventing further intestinal mucosal damage, and for therapeutic success. This study will provide a novel insight into the crucial role ClC-2 plays n intestinal barrier recovery. The proposed studies will provide us with mechanistic and potentially therapeutic information on how chloride channel ClC-2 enhances the gut barrier function.