Glutathione S-Transferase Pi in Age-Related Macular Degeneration

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是发达国家老年人失明的主要原因。氧化损伤与AMD发病机制有关。视网膜具有高的需氧量，并且由于视觉的复杂、活跃的光化学反应而处于光诱导损伤的风险中。集中在人类黄斑中的是膳食类胡萝卜素抗氧化剂叶黄素和玉米黄质，并且已经发现与老年对照眼相比，它们的水平在AMD中较低。最近，谷胱甘肽S-转移酶（GSTP 1）的pi亚型已被确定为人黄斑中的玉米黄质结合蛋白。谷胱甘肽S-转移酶是细胞内解毒酶家族，其通过将亲电体（包括反应性氧化物质）缀合至谷胱甘肽来催化亲电体的还原。GST 1已被证明在氧化损伤中起作用，并且GST 1作为玉米黄质结合蛋白的黄斑定位表明其在调节黄斑中的抗氧化剂水平中起重要作用。我们的初步数据显示，GSTP 1的表达减少，在AMD相比，正常老年人对照眼。我们推测GSTP 1表达的降低使黄斑对氧化应激敏感，导致AMD发病。长期目标是了解AMD发病机制的分子机制，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将确定人视网膜中GST 1水平的降低是否伴随年龄和AMD。具体目标2将确定小鼠视网膜中GSTP 1的鼠对应部分的减少是否将模拟小鼠中的AMD表型。具体目标3将解决GST 1过表达是否在光诱导的视网膜损伤鼠模型中提供针对氧化损伤的保护。拟定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。 公共卫生相关性：项目叙述：本研究旨在探讨谷胱甘肽S-转移酶（GSTP 1）的π亚型在老年性黄斑变性（AMD）病理学中是否在氧化损伤中发挥作用。我们将确定GSTP 1在人AMD和对照视网膜中的表达，以及与正常对照小鼠相比伴随GSTP 1过表达和减少的视网膜表型。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Project Narrative: We propose to investigate whether the pi isoform of glutathione S-transferase (GSTP1) plays a role in oxidative damage in the pathology of age-related macular degeneration (AMD). We will determine the GSTP1 expression in human AMD and control retina as well as the retinal phenotype concomitant with GSTP1 over-expression and reduction compared to normal control mice.