OXIDATIVE STRESS AND BRAIN AGING

氧化应激和大脑老化

基本信息

批准号：
7571961
负责人：
MICHAEL J. FORSTER
金额：
$ 25.37万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7571961
关键词：
Acetylcysteine Aconitate Hydratase Address Adenine Nucleotide Translocase Age Age-associated memory impairment Aging Antioxidants Attenuated Behavioral Bioenergetics Brain Brain region Caloric Restriction Cell physiology Cognition Cognitive Complex Frequencies Functional disorder Funding Glutathione Impaired cognition Impairment Insecta Intervention Measures Mediating Memory Memory impairment Mitochondria Mitochondrial Proteins Mus Neurodegenerative Disorders Oxidation-Reduction Oxidative Stress Performance Play Process Progesterone Progress Reports Proteins Psychomotor Impairments Psychomotor Performance Reactive Oxygen Species Recovery Research Research Personnel Rodent Role Signal Transduction Signaling Molecule Site Synaptic plasticity Testing Treatment Protocols age difference age effect age related aged aging brain anti aging behavioral impairment cognitive function computerized data processing enzyme activity improved loss of function macromolecule middle age motor impairment oxidation oxidative damage programs protein function research study senescence

项目摘要

The ability of reactive oxygen species (ROS) to produce dysfunctional macromolecules is thought to play a significant role in brain aging and in neurodegenerative diseases. However, it is also well established that ROS serve as important signaling molecules involved in cellular processes that underlie different cognitive functions. In the current application, it is hypothesized that age-dependent increases in ROS may cause age- associated cognitive or motor impairment by (i) promoting deleterious accumulation of oxidative damage to specific mitochondrial proteins, (ii)causing a decrease in efficiency of ROS-mediated signaling and/or(iii) initiating compensatory shifts in signaling mechanisms underlying brain processes. Under Aim 1 of this application, we will identify proteins in mitochondria from different brain regions that are associated with age- related increases in carbonyls, in aged mice with and without cognitive or motor impairments. The functional significance of these impairment-associated oxidized proteins will be addressed further under Aim 2, in which it is proposed to determine the correlation between impaired bioenergetic activity of oxidized proteins and age-related behavioral dysfunction. Aim 3 of this application will assess whether or not the age-related increase in "unregulated ROS" contributes to impairment of synaptic plasticity and memory function, and assess whether or not this contribution is age-dependent. Aim 4 of the application is to determine if behavioral impairments associatedwith ROS can be reversed by experimental interventions that produce reductive shifts in the redox state of glutathione, or promote recovery of bioenergetic functions of specific oxidized proteins. The Aim 4 studies will also address whether or not the ability of interventions to reverse age-related impairments is age-dependent. The results of these studies should refute or validate the idea that oxidative damage to specific mitochondrial proteins is a factor in age-related decrements in cognitive or psychomotor performance, and may identify specific molecules that should be targeted by anti-aging interventions. These studies will also address the hypothesis that increases in unregulated ROS directly impair cognition during aging and promote relatively non-reversible derangement of underlying signaling processes. Finally, these studies will identify periods of senescence for which antioxidative treatment of cognitive decline is most likely to be successful.

活性氧 (ROS) 产生功能失调的大分子的能力被认为在在大脑衰老和神经退行性疾病中发挥着重要作用。然而，也已经确定的是 ROS 作为重要的信号分子参与不同认知基础的细胞过程功能。在当前的应用中，假设 ROS 的年龄依赖性增加可能会导致年龄- 相关的认知或运动障碍，通过（i）促进氧化损伤的有害积累特定线粒体蛋白，(ii) 导致 ROS 介导的信号传导效率降低和/或 (iii) 启动大脑过程中信号机制的补偿性转变。在本目标 1 下应用程序，我们将识别来自不同大脑区域的线粒体中与年龄相关的蛋白质在有或没有认知或运动障碍的老年小鼠中，羰基的相关增加。功能性的这些与损伤相关的氧化蛋白的重要性将在目标 2 下进一步讨论，建议确定氧化蛋白质的生物能活性受损之间的相关性以及与年龄相关的行为功能障碍。本申请的目标 3 将评估是否与年龄相关 “不受调节的活性氧”的增加会导致突触可塑性和记忆功能受损，并且评估这种贡献是否与年龄有关。该应用程序的目标 4 是确定是否与 ROS 相关的行为障碍可以通过产生的实验干预来逆转谷胱甘肽氧化还原态的还原转变，或促进特定生物能功能的恢复氧化蛋白质。目标 4 研究还将探讨干预措施是否能够逆转与年龄相关的损伤与年龄有关。这些研究的结果应该反驳或验证这个想法对特定线粒体蛋白的氧化损伤是与年龄相关的认知或认知能力下降的一个因素精神运动表现，并可以识别抗衰老应针对的特定分子干预措施。这些研究还将解决不受调节的 ROS 直接增加的假设在衰老过程中损害认知并促进潜在信号传导相对不可逆的紊乱流程。最后，这些研究将确定抗氧化治疗的衰老时期认知能力下降最有可能成功。