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：与年龄相关的黄斑变性（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）的年龄相关变性，以及视网膜黄斑区域中的感光体。该疾病的基本机制尚不清楚。没有有效的预防策略或治疗方法。最近的研究表明，AMD的病因涉及氧化应激，RPE的损害随着年龄的增长而增加。我们假设由氧化应激引起的RPE线粒体损害有助于在AMD中观察到的视网膜变性，并且诸如α-脂肪酸，辅酶Q10和乙酰L-肉碱等化合物，这些化合物可以防止氧化损伤或减少氧化细胞。不同的线粒体养分通过不同的途径发挥保护作用。因此，这些化合物的组合可能具有添加剂或协同作用。 我们建议确定这些线粒体营养素的组合，这些养分最有效地预防和处理氧化剂诱导的线粒体损伤。提出的实验使用人胎胎RPE的汇合单层可以总结四个特定的目的：（1）当在RPE中氧化应激之前给予线粒体养分（单独和最佳组合）的保护作用（“预处理”）。 （2）确定预处理后氧化剂诱导的线粒体损伤所涉及的途径； （3）当在急性和慢性氧化剂引起的RPE中的线粒体损伤后给予线粒体养分的治疗作用（“后处理”）。 （4）确定治疗过程中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能为开发治疗剂的发展提供了基础，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。