The goal of the studies described in this proposal is the delineation of the role of peptide growth factors in mucosal repair after injury. Studies using simple in vitro models during the current support period have demonstrated that restitution, the initial stage of wound repair characterized by cellular migration to rapidly establish epithelial continuity, is controlled by several regulatory peptides, including both growth factors and cytokines. Importantly, all of these factors appear to act through transforming growth factor-beta (TGF-beta). Therefore, efforts under this proposal will focus on finding the mechanisms through which TGF-beta sustains the normal barrier and initiates restitution after injury followed by a proliferative response that reconstitutes the mucosal epithelial population. The goals of this proposal will be accomplished in three specific aims: 1). To determine the role of TFG-beta in maintaining the epithelial integrity and mucosal barrier function. This will be accomplished by using monolayers made unresponsive to TGF-beta through transfection with a """"""""dominant-negative"""""""" TGF-beta receptor and establishing a murine epithelial cell line by transgenic technology in which the epithelium has been made selectively unresponsive to TGF-beta in order to define the resulting effects on barrier function and wound healing. 2). To delineate the TFG-beta dependent mechanisms of restitution. Coordinate correlation of extracellular matrix and integrin receptors will be defined in conjunction with focal adhesion kinase and cytoskeletal structure after wounding to provide insight into the mechanisms which result in coordinate loss of cell priority and acquisition of a motile phenotype. 3). To delineate the mechanism downregulating the TGF-beta response to permit proliferative repair after restitution.
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