OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, AND AGING

氧化应激、线粒体功能障碍和衰老

• 批准号: 6168914
• 负责人: Enrique Cadenas
• 金额: $ 29.06万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 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 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6168914
• 关键词: DNA damage; aging; apoptosis; calcium flux; cellular respiration; cytochrome c; disulfide bond; free radicals; hydrogen peroxide; laboratory rat; membrane potentials; mitochondria; mitochondrial DNA; nitric oxide; oxidative stress; oxygen consumption; thiols

DESCRIPTION: (adapted from Investigator's abstract) The hypothesis to be tested is that sustained production of free radicals by mitochondria leads to critical mitochondrial DNA damage and dysfunction that are amplified to lethal cellular events by initiating apoptotic pathways through cyctochrome c release and c-jun N-terminal kinase activation. The four specific aims are: (1) To determine the effects of age on the regulation of mitochondrial functions by metabolic state, oxygen, and nitric oxide. (2) To identify the mechanisms and consequences of mitochondrial DNA (mtDNA) oxidative damage leading to specific mtDNA mutations. (3) To elucidate the consequences of mtDNA mutations at the cellular level within the framework of mitochondrial changes signaling for apoptosis. (4) To examine the role of the thiol/disulfide status in mtDNA damage and further consequences at mitochondrial and cellular levels. The focus of this research proposal is to identify the critical molecular events that are involved in the sequence from mitochondrial dysfunction to apoptosis by assessing various stimulatory and protective pathways that can initiate or delay the onset of cell death.

描述：（改编自研究者的摘要）假设 所测试的是线粒体持续产生自由基 导致严重的线粒体 DNA 损伤和功能障碍 通过启动细胞凋亡途径放大至致命的细胞事件 通过细胞色素 c 释放和 c-jun N 末端激酶激活。 四个具体目标是： (1) 确定年龄对 通过代谢状态、氧和线粒体功能的调节 一氧化氮。 (2) 确定机制和后果 线粒体 DNA (mtDNA) 氧化损伤导致特定 mtDNA 突变。 (3) 阐明线粒体DNA突变的后果 线粒体变化信号传导框架内的细胞水平 用于细胞凋亡。 (4) 考察硫醇/二硫化物状态在 mtDNA 损伤以及线粒体和细胞的进一步后果 水平。本研究计划的重点是确定关键的 线粒体序列中涉及的分子事件 通过评估各种刺激和保护作用来评估细胞凋亡的功能障碍 可以启动或延迟细胞死亡发生的途径。