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Mitochondrial Nutrients Protect RPE from Oxidant Damage

线粒体营养素保护 RPE 免受氧化损伤

基本信息

批准号：
7140454
负责人：
Bruce N Ames
金额：
$ 19.54万
依托单位：
CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-30 至 2008-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7140454
关键词：
Mitochondrial Nutrients Protect RPE Oxidant

项目摘要

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.

摘要：年龄相关性黄斑变性（AMD）是世界范围内59岁以上人群视力丧失的主要原因。它占了西方世界失明人数的50%。AMD源于视网膜黄斑区视网膜色素上皮（RPE）和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线粒体损伤有助于AMD中观察到的视网膜变性，而α -硫辛酸、辅酶Q10和乙酰左旋肉碱等保护线粒体免受氧化损伤的化合物可能预防或减轻氧化诱导的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具有加性或协同作用。