Glutathione S-Transferase Pi in Age-Related Macular Degeneration

项目摘要 视网膜相关性黄斑变性（AMD）是老年人失明的主要原因， 发达国家氧化损伤与AMD发病机制有关。视网膜有一个 高需氧量，并有光诱导损伤的风险，因为复杂的，活性的 视觉的光化学反应。集中在人类黄斑是膳食类胡萝卜素 抗氧化剂叶黄素和玉米黄质，并且已经发现它们的水平在AMD中低于对照组。 老年人控制眼睛。最近，谷胱甘肽S-转移酶（GSTP 1）的pi亚型已被鉴定 作为一种玉米黄质结合蛋白。谷胱甘肽S-转移酶是一个家族， 催化亲电体还原的细胞内解毒酶，包括反应性 氧化物种，通过将它们与谷胱甘肽结合。GSTP 1已被证明在以下方面发挥作用： 氧化损伤和作为玉米黄质结合蛋白的GST 1的黄斑定位表明， 在调节黄斑中的抗氧化剂水平方面起着重要作用。我们的初步数据 揭示了与正常老年对照眼相比，AMD中GSTP 1表达降低。我们 假设GSTP 1的表达减少使人对氧化应激敏感， 黄斑，导致AMD发病。长期目标是了解 AMD发病机制的研究，并制定有效的预防和治疗策略。 我们的假设将通过三个具体目标进行检验。具体目标1将确定是否降低 人视网膜中GSTP 1水平与年龄和AMD相关。具体目标2将决定是否 小鼠视网膜中GSTP 1的鼠对应部分的减少将模拟AMD表型， 小鼠具体目标3将解决GST 1过表达是否提供抗氧化保护， 在光诱导的视网膜损伤小鼠模型中的损伤。拟议的研究将利用临床 眼科诊断、免疫组织化学、Western分析以及电生理学。

Project Summary Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in the developed countries. Oxidative damage has been implicated in AMD pathogenesis. The retina has a high oxygen demand and is at risk for light-induced damage because of the complex, active photochemical reactions of vision. Concentrated in the human macula are dietary carotenoid antioxidants lutein and zeaxanthin, and their levels have been found to be lower in AMD compared to elderly control eyes. Recently, the pi isoform of glutathione S-transferase (GSTP1) has been identified as a zeaxanthin-binding protein in the human macula. Glutathione S-transferases are a family of intracellular detoxification enzymes that catalyze the reduction of electrophiles, including reactive oxidative species, by conjugating them to glutathione. GSTP1 has been shown to play a role in oxidative damage, and macular localization of GSTP1 as a zeaxanthin-binding protein suggests that it plays an important role in modulating the levels of antioxidants in the macula. Our preliminary data revealed that GSTP1 expression is decreased in AMD compared to normal elderly control eyes. We hypothesize that decreased expression of GSTP1 renders susceptibility to oxidative stress in the macula, leading to AMD pathogenesis. The long-term goals are to understand the molecular mechanism of AMD pathogenesis and to develop effective preventative and therapeutic strategies. Our hypothesis will be tested with three specific aims. Specific Aim 1 will determine if decreased levels of GSTP1 accompany age and AMD in human retina. Specific Aim 2 will determine whether reduction of the murine counter-part of GSTP1 in mouse retina will mimic the AMD phenotype in mice. Specific Aim 3 will address if GSTP1 over-expression provides protection against oxidative damage in a light-induced retinal damage murine model. The proposed studies will utilize clinical ophthalmic diagnosis, immunohistochemistry, Western analysis, as well as electrophysiology.