Mitochondrial Nutrients Protect RPE from Oxidant Damage

描述(由申请人提供)：摘要：老年性黄斑变性(AMD)是全球59岁以上人群视力丧失的主要原因。它约占西方世界失明人数的50%。AMD起源于视网膜黄斑区视网膜色素上皮(RPE)和感光细胞的增龄性变性。这种疾病的潜在机制尚不清楚；目前还没有有效的预防策略或治疗方法。最近的研究表明，氧化应激参与了AMD的病因，对RPE的损伤随着年龄的增长而增加。我们假设氧化应激对RPE线粒体的损伤是导致AMD视网膜变性的原因之一，保护线粒体免受氧化损伤的化合物如α-硫辛酸、辅酶Q10和乙酰基-L-肉碱可能预防或减轻氧化剂诱导的RPE细胞损伤。不同的线粒体营养物质通过不同的途径发挥其保护作用；因此，这些化合物的组合可能具有相加或协同作用。 我们建议确定在预防和治疗氧化剂诱导的线粒体损伤方面最有效的线粒体营养物质的组合。拟议的实验，使用融合的人胎儿RPE单层，可以总结为四个特定的目的：(1)确定在RPE中氧化应激之前给予线粒体营养素的单独和最佳组合的保护效果(“前处理”)。(2)确定氧化诱导的线粒体损伤的前处理途径；(3)确定线粒体营养素在急性和慢性氧化诱导的RPE线粒体损伤(“后处理”)后单独和以最佳组合给予的治疗效果。(4)明确氧化损伤后线粒体损伤的途径。这种对线粒体营养物质的体外分析可能为开发能够预防和/或减少AMD的视网膜和RPE病理生理学改变的治疗剂提供基础。

DESCRIPTION (provided by applicant): Summary: Age-related macular degeneration (AMD) is a leading cause of vision loss world-wide among people over 59. It accounts for approximately 50% of the blindness in the Western world. AMD stems from the age-related degeneration of retinal pigment epithelium (RPE) and the photoreceptors in the macular area of the retina. The underlying mechanism of this disease is unclear; there are no effective preventive strategies or treatments. Recent studies suggest that oxidative stress is involved in the etiology of AMD, and that damage to RPE increases with age. We hypothesize that damage to RPE mitochondria caused by oxidative stress contributes to the retinal degeneration observed in AMD and that compounds such as alpha-lipoic acid, coenzyme Q10, and acetyl-L-carnitine, which protect mitochondria against oxidative insult, may prevent or lessen oxidant induced RPE cellular damage. Different mitochondrial nutrients exert their protective effects via different pathways; thus, combinations of these compounds may have additive or synergistic effects. We propose to identify the combinations of these mitochondrial nutrients that are most effective in preventing and treating oxidant-induced mitochondrial damage. The proposed experiments, using confluent monolayers of human fetal RPE, can be summarized in four Specific Aims: (1) Determine the protective effects of mitochondrial nutrients, both individually and in optimal combinations, when administered prior to oxidative stress in RPE ("pretreatment"). (2) Identify the pathways involved in oxidant-induced mitochondrial damage following pretreatment; (3) Determine the therapeutic effects of mitochondrial nutrients, both individually and in optimal combinations, when administered following acute and chronic oxidant-induced mitochondrial damage in RPE ("post-treatment"). (4) Identify the pathways involved in oxidant-induced mitochondrial damage during post-treatment. This in vitro analysis of mitochondrial nutrients may provide the basis for the development of therapeutic agents that can prevent and/or reduce the retinal and RPE pathophysiology observed in AMD.