OXIDATIVE INJURY IN THE CENTRAL NERVOUS SYSTEM IN AD, PD, AND ALS

AD、PD 和 ALS 中枢神经系统的氧化损伤

• 批准号: 6098633
• 负责人: Robert H. Brown
• 金额: $ 17.77万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 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 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098633
• 关键词: Alzheimer's disease; DNA damage; Parkinson's disease; aging; amyotrophic lateral sclerosis; antioxidants; antisense nucleic acid; biomarker; carbonyl group; disease /disorder model; enzyme activity; free radical oxygen; genetically modified animals; histopathology; human genetic material tag; human tissue; laboratory mouse; laboratory rat; lipid peroxides; model design /development; neural degeneration; oxidative stress; peroxidation; postmortem; superoxide dismutase

Oxidative stress from endogenous and exogenous oxidants has been implicated as a major determinant of aging and as a causative factor in Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). The possibility that oxidative neuronal damage might cause neurodegenerative diseases was recently strengthened by the observation that the free radical scavenging enzyme Cu/Zn superoxide dismutase (SOD1) is mutated in some individuals with inherited ALS. This project will utilize neurochemical and histological studies to assess oxidative stress in postmortem brain tissue from normal individuals with aging and patients with neurodegenerative diseases. The Specific Aims are to: (1) determine whether there is increased oxidative damage to proteins, lipid or DNA, and whether there are altered antioxidant enzyme activities in postmortem brain tissue of individuals with neurodegenerative diseases and normal aging, (2) utilize histological techniques to study oxidative damage in specific populations of neurons vulnerable to the neurodegenerative diseases; (3) determine whether biochemical markers of oxidative damage are increased in plasma and urine of patients with AD, PD and ALS; and (4) develop animal models of oxidative stress using antisense DNA to SOD1 and transgenic mice either oxer-expressing mutant forms of SOD1 or with targeted inactivation of SOD1. The proposed studies will provide a direct assessment of markers of oxidative stress in postmortem tissue in normal individuals with aging and in AD, PD and ALS patients. The combined neurochemical and histological studies will characterize the nature and distribution of the oxidative injury at the cellular level. Moreover, our studies will allow development of reliable markers for oxidative stress in both plasma and urine of patients with neurodegenerative diseases. Such markers may be useful both for diagnostic purposed and for monitoring both disease progression and the effects of therapy. Lastly, the animal models we propose to develop should be powerful tools both for studying the biochemical and molecular pathophysiology of oxidative neuronal toxicity and for trials of new therapies.

来自内源性和外源性氧化剂的氧化应激 被认为是衰老的主要决定因素和导致衰老的因素 阿尔茨海默病 (AD)、帕金森病 (PD) 和肌萎缩症 侧索硬化症（ALS）。氧化性神经元损伤的可能性 可能导致神经退行性疾病最近得到了加强 观察自由基清除酶 Cu/Zn 超氧化物 歧化酶 (SOD1) 在某些患有遗传性 ALS 的个体中发生突变。 这 项目将利用神经化学和组织学研究来评估 正常个体死后脑组织中的氧化应激 老龄化和神经退行性疾病患者。 具体目标 目的是：（1）确定氧化损伤是否增加 蛋白质、脂质或DNA，以及是否存在改变的抗氧化酶 患有此病的个体死后脑组织的活动 神经退行性疾病和正常衰老，（2）利用组织学 研究特定神经元群氧化损伤的技术 易患神经退行性疾病； (3)判断是否 血浆和尿液中氧化损伤的生化标志物增加 AD、PD 和 ALS 患者； (4) 开发动物模型 使用 SOD1 反义 DNA 和转基因小鼠进行氧化应激 oxer 表达 SOD1 突变体或靶向失活 超氧化物歧化酶1。 拟议的研究将提供标记物的直接评估 正常衰老个体死后组织氧化应激的影响 以及 AD、PD 和 ALS 患者。 结合神经化学和 组织学研究将表征其性质和分布 细胞水平的氧化损伤。 此外，我们的研究将允许 开发血浆和氧化应激的可靠标记物 神经退行性疾病患者的尿液。 此类标记可能是 对于诊断目的和监测两种疾病都很有用 进展和治疗效果。 最后是我们的动物模型 建议开发应该是强大的工具，既可以用于研究 氧化神经元毒性的生化和分子病理生理学 以及新疗法的试验。