The applicant proposes basic biologic studies of the role of the RPE cell in the pathogenesis of PVR. The importance of leukocytes and their cytokine products in the development of PVR has previously been shown, as well as how these cytokines influence the phenotype and function of RPE cells. In PVR, RPE become embedded in an extracellular matrix (ECM) through which they must invade in order for PVR to develop. Three hypotheses will be tested concerning the mechanisms and post-receptor signaling pathways involved in cytokine regulation of RPE invasion of the ECM: (1) cytokines regulate adhesion to the ECM by stimulating RPE expression of integrins and ECM receptors; (2) chemotactic migration of RPE is mediated through activation of the mitogen-activated protein kinase (MAPK) pathway by stimulation of cytokine receptors, adhesion to the ECM, and convergence of other signaling pathways (PKC, focal adhesion kinase); and (3) invasion of the ECM by RPE is increased by cytokine stimulation of proteolysis and ECM phagocytosis at the sites of adhesion. To test these hypotheses the applicant will study the mechanism by which platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and tumor necrosis factor-alpha (TNF) modulate MAPK activity in human RPE cells and how these cytokines regulate RPE adhesion, migration, proteolysis, and invasion into various substrates. Finally, the applicant will test the significance of these findings by attempting to inhibit in vivo RPE invasion and experimental PVR using novel signal transduction therapy and gene therapy approaches.
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