Mitochondrial Nutrients Protect RPE from Oxidant Damage

线粒体营养素保护 RPE 免受氧化损伤

• 批准号: 6967342
• 负责人: Bruce N Ames
• 金额: $ 20.01万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6967342
• 关键词: Mitochondrial; Nutrients; Protect; RPE; Oxidant

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.

描述（由申请人提供）： 摘要：年龄相关性黄斑变性 (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的 50%。 AMD 源于视网膜色素上皮 (RPE) 和视网膜黄斑区感光细胞与年龄相关的变性。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，氧化应激与 AMD 的病因有关，并且 RPE 的损伤随着年龄的增长而增加。我们假设氧化应激引起的 RPE 线粒体损伤会导致 AMD 中观察到的视网膜变性，而α-硫辛酸、辅酶 Q10 和乙酰基-L-肉碱等化合物可以保护线粒体免受氧化损伤，可以预防或减轻氧化剂诱导的 RPE 细胞损伤。不同的线粒体营养物质通过不同的途径发挥保护作用；因此，这些化合物的组合可以具有相加或协同效应。 我们建议确定这些线粒体营养素的组合，以最有效地预防和治疗氧化剂引起的线粒体损伤。所提出的实验使用人类胎儿 RPE 的汇合单层，可概括为四个具体目标：（1）确定在 RPE 氧化应激之前施用（“预处理”）时单独和最佳组合的线粒体营养素的保护作用。 (2) 确定预处理后参与氧化剂诱导线粒体损伤的途径； (3) 确定在 RPE 中急性和慢性氧化剂诱导的线粒体损伤（“治疗后”）后施用线粒体营养素的治疗效果，无论是单独的还是最佳组合。 (4) 确定治疗后氧化剂诱导线粒体损伤的途径。这种线粒体营养素的体外分析可以为开发治疗剂提供基础，这些治疗剂可以预防和/或减少 AMD 中观察到的视网膜和 RPE 病理生理学。