ANTIOXIDANT SYSTEMS AND AGE RELATED MACULAR DEGENERATION

抗氧化系统和年龄相关性黄斑变性

• 批准号: 2161755
• 负责人: PAUL STERNBERG
• 金额: $ 22.89万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2161755
• 关键词: age difference; aging; antioxidants; ascorbate; calcium transporting ATPase; cellular pathology; glutathione; human old age (65+); human subject; human therapy evaluation; human tissue; macular degeneration; nutrition related tag; oxidative stress; peptide hormone metabolism; retinal pigment epithelium; sodium potassium exchanging ATPase; tissue /cell culture; tocopherols; vitamin therapy

Age-related macular degeneration (ARMD) is the leading cause of vision loss in elderly Americans. The photoreceptor damage that results in blindness in ARMD is usually secondary to injured retinal pigment epithelial (RPE) cells. There is substantial circumstantial data to support the hypothesis that ARMD may be related to oxidative injury and that RPE cells exhibit early signs of the disease. We now have data directly showing glutathione (GSH) to be an important antioxidant capable of protecting cultured human RPE cells from oxidative injury. In addition, preliminary studies demonstrate that plasma levels of GSH decrease with age and that there may be lower plasma GSH levels in ARMD patients. In this application, we propose to further define the role of GSH in protection of the RPE from oxidative injury. Two groups of studies will be performed to evaluate the effects of aging and ARMD on GSH: l) blood levels of GSH will be measured in a cohort of patients without ARMD as well as those with well characterized ARMD, including a sub-population of patients not taking micronutrient antioxidant supplementation, and 2) GSH synthetic capacity will be determined in eyes of donors of varying ages, with and without ARMD by measuring the rate of GSH synthesis and activity of the enzyme catalyzing GSH synthesis, gamma-glutamycysteine synthetase (GCS), in cultured RPE cells, and by measurement of mRNA for GCS in fresh RPE from autopsy eyes. Further studies will be performed to determine whether GSH synthetic capacity can be manipulated therapeutically using different GSH precursors, hormonal inducers, or phenolic antioxidants that may induce GCS activity. Finally, mechanistic studies will establish l) whether improved maintenance of intracellular GSH leads to increased peroxide elimination and better maintenance of the intracellular antioxidants, ascorbate and alpha-tocopherol, and 2) whether exogenous GSH can protect by preventing damage to two critical plasma membrane transport systems, Na+,K+ATPase and Ca2+-ATPase. The results of these studies will provide critical data to help in our understanding of the pathogenesis of ARMD and could provide the platform for future therapies.

年龄相关性黄斑变性（ARMD）是导致视力下降的主要原因 美国老年人的损失。感光细胞损伤导致 ARMD 患者的失明通常继发于视网膜色素损伤 上皮（RPE）细胞。 有大量间接数据可以证明 支持ARMD可能与氧化损伤有关的假设 RPE 细胞表现出疾病的早期迹象。 我们现在有数据 直接表明谷胱甘肽 (GSH) 是一种重要的抗氧化剂 保护培养的人 RPE 细胞免受氧化损伤。此外， 初步研究表明血浆 GSH 水平随 ARMD 患者的年龄和血浆 GSH 水平可能较低。 在此应用中，我们建议进一步定义 GSH 在 保护 RPE 免受氧化损伤。 两组研究将 用于评估衰老和 ARMD 对 GSH 的影响： l) 血液 将在一组没有 ARMD 的患者中测量 GSH 水平，如下所示： 以及那些具有明确特征的 ARMD 的人，包括 未服用微量营养素抗氧化剂补充剂的患者，以及 2) GSH 合成能力将根据不同年龄的捐赠者的眼光来确定， 通过测量 GSH 合成率和活性来评估有或没有 ARMD 催化 GSH 合成的酶，γ-谷氨酰胺半胱氨酸合成酶 (GCS)，在培养的 RPE 细胞中，以及通过测量新鲜细胞中 GCS 的 mRNA 来自尸检眼睛的 RPE。 将进行进一步的研究以确定 是否可以通过治疗来控制 GSH 合成能力 不同的谷胱甘肽前体、激素诱导剂或酚类抗氧化剂 可能会诱导 GCS 活性。 最后，机制研究将建立 l) 改善细胞内 GSH 的维持是否会导致 消除过氧化物并更好地维护细胞内 抗氧化剂、抗坏血酸和 α-生育酚，以及 2) 是否外源性 GSH 可以通过防止两个关键质膜运输受损来提供保护 系统，Na+、K+ATP酶和Ca2+-ATP酶。 这些研究的结果将提供关键数据来帮助我们 了解ARMD的发病机制并可以提供平台 用于未来的治疗。