Mitochondrial Nutrients Protect RPE from Oxidant Damage

描述（由申请人提供）：摘要：视网膜相关性黄斑变性（AMD）是世界范围内59岁以上人群视力丧失的主要原因。它占西方世界失明人数的约50%。AMD源于视网膜色素上皮（RPE）和视网膜黄斑区中的光感受器的年龄相关性变性。这种疾病的潜在机制尚不清楚;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AMD的病因学，并且对RPE的损伤随着年龄的增长而增加。我们假设由氧化应激引起的对RPE线粒体的损伤有助于在AMD中观察到的视网膜变性，并且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-L-肉毒碱可以预防或减轻氧化剂诱导的RPE细胞损伤。不同的线粒体营养素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累加或协同作用。 我们建议确定这些线粒体营养素的组合，最有效地预防和治疗氧化剂诱导的线粒体损伤。使用人胎儿RPE的汇合单层的所提出的实验可以总结为四个具体目的：（1）确定当在RPE中的氧化应激之前施用（“预处理”）时，线粒体营养物单独地和以最佳组合的保护作用。(2)确定预处理后氧化剂诱导的线粒体损伤中涉及的途径;（3）确定当在RPE中急性和慢性氧化剂诱导的线粒体损伤后（“治疗后”）施用时，线粒体营养物单独和以最佳组合的治疗效果。(4)确定后处理期间氧化剂诱导的线粒体损伤所涉及的途径。线粒体营养素的这种体外分析可以为开发可以预防和/或减少在AMD中观察到的视网膜和RPE病理生理学的治疗剂提供基础。

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.