APOPTOSIS BY FAS IN HUMAN RETINAL PIGMENT EPITHELIUM

本研究提出Fas介导的细胞凋亡导致人RPE （hRPE）氧化损伤，从而导致年龄相关性黄斑变性（ARMD）的假说。先前的研究表明，RPE的丧失是ARMD的关键早期事件，间接证据表明氧化机制参与其中。本课课组近期研究表明，氧化诱导的hRPE细胞死亡可能涉及两种机制，线粒体介导的细胞凋亡激活和fas介导的细胞凋亡激活。拟开展的研究将确定1)Fas的激活是否在氧化诱导的hRPE细胞凋亡中作用于线粒体上游的主要机制，2)与衰老相关的生理过程是否增强了Fas在培养的hRPE中介导的细胞死亡，以及3)人体血液中FasL（血浆中的sFasL和单核细胞中的FasL）的浓度和变化是否足以保证血液中FasL与ARMD之间潜在关联的临床研究。虽然这些目标的成功完成不能指望建立ARMD的机制，但它们将为fas介导的细胞凋亡在疾病过程中发挥核心作用的可能性提供重要信息。

This research proposal focuses on the hypothesis that Fas- mediated apoptosis contributes to oxidative injury of human RPE (hRPE) and thereby could contribute to age-related macular degeneration (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. Recent studies from this research group have shown that oxidant-induced cell death in hRPE may involve 2 mechanisms, activation of mitochondria-mediated apoptosis and activation of Fas-mediated apoptosis. The proposed research will determine 1) whether activation of Fas is a principal mechanism acting upstream of mitochondria in oxidant-induced apoptosis in hRPE, 2) whether physiologic processes associated with aging potentiate cell death mediated by Fas in cultured hRPE and 3) whether there is a sufficient concentration and variation in human blood levels of FasL (sFasL in plasma and FasL in monocytes) to warrant clinical studies of the potential association between blood FasL and ARMD. 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.