Glutathione S-Transferase Pi in Age-Related Macular Degeneration

谷胱甘肽 S-转移酶 Pi 在年龄相关性黄斑变性中的作用

• 批准号: 8305622
• 负责人: Wen-Hsiang Lee
• 金额: $ 20.98万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305622
• 关键词: Address; Age; Age related macular degeneration; Aging; Antioxidants; Binding Proteins; Biological Assay; Blindness; Carotenoids; Clinical; Complex; Data; Developed Countries; Diagnosis; Dietary Carotenoid; Drug Metabolic Detoxication; Elderly; Electrophysiology (science); Enzymes; Epithelial; Eye; Family; GSTP1 gene; Glutathione; Glutathione S-Transferase; Goals; Homologous Gene; Human; Immunohistochemistry; Isomerism; Knock-out; Knockout Mice; Light; Lutein; Mediating; Metabolism; Modeling; Molecular; Mus; Oxidative Stress; Oxygen; Pathogenesis; Pathology; Phenotype; Play; Predisposition; Protein Isoforms; Reaction; Retina; Retinal; Risk; Role; Severities; Staging; Testing; Therapeutic; Tissues; Viral Vector; Visible Radiation; Vision; Western Blotting; Xanthophylls; glutathione S-transferase pi; inhibitor/antagonist; macula; mouse model; oxidative damage; retinal damage; small hairpin RNA; uptake; zeaxanthin

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.

项目概要 年龄相关性黄斑变性（AMD）是导致老年人失明的主要原因 发达国家。 AMD 发病机制涉及氧化损伤。视网膜有一个 高需氧量，并且由于复杂的活性物质而面临光诱导损伤的风险 视觉的光化学反应。膳食类胡萝卜素集中在人类黄斑中 抗氧化剂叶黄素和玉米黄质，与 AMD 相比，它们的水平较低 老年人控制眼睛。最近，谷胱甘肽S-转移酶（GSTP1）的pi亚型已被鉴定 作为人类黄斑中的玉米黄质结合蛋白。谷胱甘肽 S-转移酶是一个家族 细胞内解毒酶，催化亲电子试剂的减少，包括反应性试剂 氧化物质，通过将它们与谷胱甘肽结合。 GSTP1 已被证明在以下方面发挥作用： 氧化损伤以及 GSTP1 作为玉米黄质结合蛋白的黄斑定位表明 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 研究表明，与正常老年对照眼相比，AMD 中 GSTP1 的表达降低。我们 假设 GSTP1 表达减少会导致机体对氧化应激更加敏感 黄斑，导致AMD发病机制。长期目标是了解分子 AMD发病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 将确定是否减少 人类视网膜中 GSTP1 的水平与年龄和 AMD 相关。具体目标 2 将决定是否 小鼠视网膜中 GSTP1 的小鼠对应部分的减少将模拟 AMD 的表型 老鼠。具体目标 3 将解决 GSTP1 过度表达是否能提供抗氧化保护 光诱导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。