The overall goal of this project is to determine the important cellular and molecular events during tissue repair and the local response to tumors and how they may be beneficially influenced by intervention. The cellular events that occur in the course of skin and corneal wound healing in animals will be analyzed systematically, with emphasis on matrix attachment components such as fibronectin and laminin and their receptors and determine how they may be altered by growth factors, particularly platelet derived growth factor (PDGF). The kinetics, distribution, and identity of cells that synthesize various fibronectin and PDGF and certain other matrix and growth factor molecules will be determined in pig skin and rabbit corneal wounds, using in situ hybridization with cDNA probes, immunoperoxidase, biochemical analysis and immunogold electron microscopy. The response of these wounds to recombinant PDGF, IGF- 1, EGF or TGF-beta alone or in combination will be tested. The anatomical relationship between the laminin, fibronectin and the cellular distribution of their receptors will be determined by immunogold electron microscopy. Antagonists to laminin and fibronectin receptors in the form of F(ab')2 antibodies or synthetic peptides will be used to determine the importance of cell attachment to this substrates in vivo. The biologic importance of binding of growth factors to matrix components, such as PDGF to collagen, will be examined. In vitro tests of epithelial migration and attachment will be developed using corneal organ culture and dissociated epithelial cells to determine the mechanisms by which fibronectin promotes epithelial healing in alkali burns. The connective tissue response around human tumors will be studied with the same cDNA and antibody probes to compare with the events that occur in normal healing. The proposed studies should provide in vivo relevance to phenomena hitherto observed in vitro. Advances in the understanding of repair processes and their control should lead to more rational intervention in wounds, chronic inflammatory processes and neoplasia.
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