Apoptosis by Fas in Human Retinal Pigment Epithelium

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DESCRIPTION (provided by applicant): The purpose of this research proposal is to test the hypothesis that Fas-mediated apoptosis contributes to the death of RPE cells in ARMD. Previous research has shown that loss of RPE is a pivotal early event in ARMD and circumstantial evidence indicates that oxidative mechanisms are involved. The recently published results from AREDS have demonstrated that antioxidants vitamins and zinc significantly reduce risk of vision loss from ARMD, which has provided a strong evidence that oxidative stress plays an important role in ARMD. My study has shown that Fas ligand/Fas mediates apoptosis and oxidant-induced cell death in cultured human RPE (hRPE) cells. Changes in the intracellular and extracellular redox status regulate Fas-mediated apoptosis and modulate the susceptibility to oxidative injury in hRPE cells. The research in the extend year will determine 1) whether Fas pathway is responsible for oxidant-induced mitochondrial changes in hRPE, 2) whether there is a change of FasL in plasma and circulating blood cells between non-ARMD and ARMD subjects, 3) whether blood cells induced to express high FasL cause apoptosis in cultured hRPE cells. Although the successful completion of these aims cannot be expected to establish a mechanism for ARMD, they will provide important information on the possibility that Fas-mediated apoptosis plays a central role in the disease process.