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.
Defective intestinal barrier allows penetration of harmful luminal antigens in the gut which in turn leads to intestinal inflammation. Recent studies have shown an integral role of ion transporters in intestinal tight junction regulation. The purpose of this grant application is to elucidate the mechanisms involved in chloride channel ClC-2-mediated enhancement of the intestinal epithelial tight junction barrier recovery. Clinically, repar 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 in intestinal barrier recovery.