NEURODEGENERATION AND MITOCHONDRIAL DYSFUNCTION IN AGING

衰老过程中的神经退行性变和线粒体功能障碍

• 批准号: 6509656
• 负责人: STEPHEN C BONDY
• 金额: $ 32.72万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6509656
• 关键词: aging; behavior test; cell line; cell senescence; cellular pathology; cysteine endopeptidases; dietary supplements; gene deletion mutation; genetically modified animals; laboratory mouse; learning; lipid peroxides; membrane structure; memory; mitochondria; mitochondrial DNA; mitochondrial membrane; neural degeneration; neurons; neuropathology; neuropharmacology; nucleic acid structure; nutrition related tag; oxidative stress

DESCRIPTION: (Verbatim from the Applicant's Abstract) neurodegenerative diseases involve promotion of a pathological process by events associated with normal aging. Senescence is generally an essential concomitant of the progression of neurological disease and if this were retarded, the incidence of many such disorders would be significantly reduced. Prevention of deficits is more readily accomplished than attempts to compensate for impaired neurological function. This application posits that the cerebral mitochondrion is a susceptible target of age-related pro-oxidant events within the CSN, that the administration of exogenous factors may modify the velocity of these events and that this can influence other biological and behavioral consequences of aging. Maturational changes in mitochondrial function, structural integrity and mtDNA characteristics will be studied throughout the lifespan of C57BL/6 mice. Attempts to retard the onset of changes in mitochondrial parameters including gene deletions, membrane stability and levels of key enzymes, will be made by dietary supplementation with antioxidants, specifically targeted toward protection against free radicals produced by the reduced efficiency of the respiratory chain encountered with advancing age. Results will be substantiated with those obtained from mitochondria derived from neural cell lines exposed to low oxidant conditions for several generations. The role of both active oxygen and nitrogen species as contributory factors in these events and their potential modulation by antioxidants will be taken into account. The protective potential of antioxidants in combination, targeted toward several sources of oxidative events, will be evaluated. While the onset of neurological disease generally does not represent merely an acceleration of normal aging, there may be biological loci common to both. The identification and protection of such common targets will help in the development of agents that can reduce the incidence of neurodegenerative disorders.

描述：（逐字摘自申请人摘要）神经退行性 疾病涉及事件促进病理过程 与正常衰老有关。衰老通常是一个必不可少的过程 伴随神经系统疾病的进展，如果这是 迟缓，许多此类疾病的发生率将显着增加 减少。预防赤字比预防赤字更容易 尝试补偿受损的神经功能。这 应用假设大脑线粒体是一种易感细胞 CSN 内与年龄相关的促氧化事件的目标，即 外源因素的施用可能会改变这些速度 事件，并且这可以影响其他生物和行为 衰老的后果。 线粒体功能、结构完整性和功能的成熟变化 mtDNA 特征将在 C57BL/6 的整个生命周期中进行研究 老鼠。尝试延缓线粒体变化的发生 参数包括基因缺失、膜稳定性和 关键酶，将通过膳食补充抗氧化剂来制造， 专门针对产生的自由基的保护 由于呼吸链效率降低 年龄的增长。结果将通过以下获得的结果得到证实 源自暴露于低氧化剂的神经细胞系的线粒体 几代人的条件。活性氧和活性氧的作用 氮物种作为这些事件的促成因素及其 将考虑抗氧化剂的潜在调节。这 抗氧化剂组合的保护潜力，针对 将评估氧化事件的几个来源。 虽然神经系统疾病的发作一般并不代表 只是正常衰老的加速，可能存在生物位点 两者共有。此类共同目标的识别和保护 将有助于开发可以减少发病率的药物 神经退行性疾病。