Apoptosis by Fas in Human Retinal Pigment Epithelium

描述(申请人提供)：本研究提案的目的是验证Fas介导的细胞凋亡导致ARMD中RPE细胞死亡的假设。先前的研究表明，RPE的丢失是ARMD的关键早期事件，间接证据表明RPE的丢失与氧化机制有关。AREDS最近发表的研究结果表明，抗氧化剂维生素和锌显著降低了ARMD导致视力丧失的风险，这为氧化应激在ARMD中发挥重要作用提供了强有力的证据。我的研究表明Fas配体/Fas介导了培养的人视网膜色素上皮(HRPE)细胞的凋亡和氧化剂诱导的细胞死亡。细胞内和细胞外氧化还原状态的变化调节Fas介导的细胞凋亡，并调节hRPE细胞对氧化损伤的敏感性。未来一年的研究将确定1)Fas通路是否参与氧化剂诱导的hRPE线粒体的改变，2)非ARMD患者和ARMD患者之间血浆和循环血细胞中FasL的变化，3)诱导高表达FasL的血细胞是否导致培养的hRPE细胞凋亡。虽然这些目标的成功完成不能期望建立ARMD的机制，但它们将提供关于Fas介导的细胞凋亡在疾病过程中发挥核心作用的可能性的重要信息。

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.