The overall goal of this proposal is to define the molecular basis of interactions between neutrophils (PMN) and epithelial cells that serve to regulate the process of PMN migration across the intestinal epithelium. The importance of PMN in epithelial pathophysiology is apparent in a number of inflammatory human diseases such as ulcerative colitis and Crohn's disease. Key features of these diseases include infiltration of intestinal mucosa by large numbers of PMN resulting in enhanced permeability, altered epithelial intercellular junctions and epithlelial erosion/ulceration. Although the pathologic consequences are well known, the molecular mechanisms regulating transepithelial migration of PMN are just beginning to be defined. Using a well established in-vitro model of PMN transepithelial migration, we have previously shown that initial adhesive events are dependent on CD11 b/CD18 whereas subsequent transmigration is dependent on CD47 interactions with its cellular receptor SIRP alpha. In this proposal we present strong evidence to support the roles of additional receptor-ligand interactions between PMN and epithelial cells at the level of epithelial intercellular junctions. Our data indicate that these receptor ligand pairs are part of the CTX family of proteins that contains all of the JAM family of proteins. Our working hypothesis is that PMN transmigration across the intestinal epithelium is a multistep process that is dependent on multiple interactions with proteins involved in regulation of intercellular junctions. To this end, we will; 1) define the role of epithelial JAM-C in the process of PMN transepithelial migration in concert with, 2) studies aimed at defining it's function in intestinal epithelial cells. In addition we will; 3) examine the roles of other JAM-like CTX proteins in regulating PMN migration across intestinal epithelia and how inflammatory mediators affect this. Characterization of such events will improve our understanding of the biology of mucosal inflammation and provide ideas for new anti-inflammatory therapies.
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