The intestinal mucosa constitutes an immunological organ were oral tolerance and defense against harmful organisms develops. For antigens to interact with dendritic antigen-presenting cells, these proteins must cross the intestinal epithelium in a controlled manner. The regulation of the intestinal epithelial cell barrier is therefore central to the development intestinal immunity and inflammation, but the mechanisms are largely unknown. The tight junctional complex is a specialized membrane domain at the most apical region of polarized epithelial cells that not only creates the primary barrier to prevent paracellular transport of solutes and pathogens but also restricts that later diffusion of membrane lipids and proteins to maintain the cellular polarity. Preliminary experiments demonstrate that members of the recently identified claudin family of tight junction associated proteins are expressed in human intestinal epithelial cells of the small and large intestine. In addition, the expression of claudins can be regulated by inflammatory mediators together with the development of transepithelial resistance in intestinal epithelial cells. Bacterial toxins can bind to claudins thus pathogens may be able to target tight junction associated proteins directly to alter intestinal epithelial cell function. However, the mechanisms regulating claudin expression during intestinal epithelial cell differentiation and the role of claudins in the regulation of the intestinal epithelial barrier during host defense is unknown. The overall hypothesis is that mechanisms regulating the expression and the cellular distribution of claudins in intestinal epithelial cells are essential to maintain the intestinal barrier. The overall goals of this proposal are to characterize the biological functions of claudins in intestinal epithelial cells and to define the cytokine and endotoxin induced molecular mechanisms, which regulate claudin expression in intestinal epithelial cells.
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