Polarity proteins and intestinal mucosal responses to inflammation and injury

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Abstract The gastrointestinal epithelium plays a central role in maintaining barrier function while coordinating mucosal homeostasis and immunity. An important negative consequence of excessive inflammation, ischemia, certain infections, and other clinical conditions is mucosal epithelial injury and wounding that serves to compromise the epithelial barrier which is tightly regulated by intercellular junctions that include the tight junction (TJ) and adherens junction (AJ), collectively referred to as the Apical Junctional Complex (AJC). Proteins involved in regulating epithelial polarity such as the Crumbs family of proteins, influence organization and function of the AJC and regulate epithelial homeostasis and differentiation. Since most of studies on polarity proteins have been performed in model organisms and transformed cell lines, current knowledge of the molecular basis by which polarity proteins orchestrate intestinal epithelial barrier function and wound repair in vivo in mammals remains limited. The overall goal of this proposal is to identify how the polarity protein Crumbs 3 (CRB3) controls epithelial homeostasis, namely barrier function and wound repair in vivo using CRB3 transgenic mice and natural human and murine intestinal epithelium. Our overarching hypothesis is that CRB3 functions as a master regulator of intestinal epithelial barrier function and wound repair by controlling assembly of different adhesion-cytoskeletal modules at the plasma membrane. Knowledge gained from these studies in the short term will provide important new insights on basic mechanisms by which polarity proteins regulate the intestinal epithelial barrier and repair. In the long term, these studies will likely provide ideas for development of new therapeutic strategies aimed at strengthening the epithelial barrier and in promoting intestinal mucosal wound repair.