The gastrointestinal epithelium functions as an important barrier that separates luminal contents from underlying tissue compartments. Disruption of epithelial barrier in ischemic disease and inflammatory bowel diseases results in fluid/electrolyte loss and exposure of tissues to luminal pathogens. To rapidly reseal such wounds epithelial cells migrate in a process termed """"""""restitution"""""""". During restitution, epithelial cells undergo significant changes in shape as they migrate in a cohesive sheet to rapidly cover denuded surfaces. Migrating cells communicate with the underlying matrix via focal cell matrix associations consisting of focal complexes (FACs) and ezrin/radixin/moesin complexes (ERM). In such adhesive contacts the actin cytoskeleton affiliates with transmembrane integrins via linker proteins that in turn provide the transient anchor required for forward cell movement. The long-term goal of this application is to understand mechanisms by which the actin cytoskeleton coordinates events between cell-matrix associations and cell-cell junctions so as to achieve efficient migration of the epithelium and wound closure. Thus we will explore the dynamic re-organization of focal-cell matrix and cell-cell associations. Membrane targeting pathways ofintegrins in FACs/ERMs to sites of cell-matrix adhesion and their recycling in endocytic pathways will be explored using morphologic, biochemical and molecular approaches. In addition, we will define function of a key intercellular junction protein, JAM-1 in regulating intercellular adhesions of a migrating epithelium. Lastly, using a transfection approach we will analyze function of Rho GTPases in regulating actin cytoskeletal events that in turn influence cell-matrix and cell-cell adhesion of a migrating epithelium. Information from the proposed studies should provide insights into mechanisms by which an epithelium migrates to reseal wounds and may yield new ideas for therapeutic agents aimed at promoting intestinal epithelial wound closure.
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