Reactive Oxygen Species and Aging

活性氧与老化

• 批准号: 7595798
• 负责人: ELIAS K MICHAELIS
• 金额: $ 145.28万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-15 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595798
• 关键词: Reactive; Oxygen; Species; Aging

DESCRIPTION (provided by applicant): Research into the molecular, genetic, and cellular aspects of aging has greatly expanded our understanding of the basic processes that contribute to both longevity and age-related diseases. The primary focus of this Program since its inception is the assertion that age-dependent increases in oxidative stress and alterations in cellular Ca2+-handling converge to produce several of the well-known manifestations of aging, such as progressive muscle weakness and compromised cognitive performance. Our past efforts have led to the identification of protein markers of oxidative stress and the characterization of the effects of oxidation and aging on critical Ca -regulating proteins, using both in vivo and in vitro models of aging. We also made a number of important observations supporting the occurrence of oxidative modifications on proteins involved in Ca2+signaling in aging tissues. Over the past few years, enormous shifts have occurred in the overall research enterprise, primarily due to the sequencing of the human genome and development of new technologies for the analysis of transcriptional, translational, and signaling events occurring in cells and tissues. As a result, the strategies that Program participants are using to study the aging process have evolved to take advantage of the latest research advances. The major theme for the overall research effort, though, continues to be oxidative stress and Ca2+ regulation in aging. New approaches involving sub-proteomic studies of protein complexes, genomics, and transgenic mouse models of metabolic stress and recovery of structure and function, are now integral components of the research in this Program. The application is a resubmission for renewal of the Program Project and consists of 3 Projects: Project 1, Sarcopenia and Apoptosis: Role of SERCA and Bcl-2; Project 2, Age-Dependent Changes in Synaptic Raft Domains and Plasma Membrane Ca2+-ATPase; Project 3, Glutamate Neurotransmission, Aging, Longevity and Neurite Remodeling. The activities of the 2 scientific Cores have been expanded to provide new services and essential expertise needed to accomplish the aims of the projects. Core B was expanded to include detailed lipid analyses of neuronal membranes from aging tissues and protein isotopic labeling methods for quantification of protein changes. Electron microscopy and quantitative imaging were added to Core C. Core A, B and C were all expanded to include enhanced data sharing, relational databases, and bioinformatics analytical tools for systematic integration of the information from the Projects. The short term objectives for the Program are to define the molecular changes in neurons and muscle cells during aging that bring about altered control of intracellular Ca2+, metabolic stress, oxidative stress, initiation of apoptotic events, and cell recovery processes. The long-term objectives are to characterize the molecular events involved in the induction of two debilitating conditions of the aged, sarcopenia (muscle cell loss/ loss of muscle strength) and selective neurodegeneration. It is hoped that defining the molecular and cellular processes that produce these conditions of aging may lead to the discovery of new targets for future therapeutic interventions.

描述（由申请人提供）：对衰老的分子、遗传和细胞方面的研究极大地扩展了我们对导致长寿和年龄相关疾病的基本过程的理解。该计划自启动以来的主要焦点是断言氧化应激的年龄依赖性增加和细胞 Ca2+ 处理的改变共同产生了一些众所周知的衰老表现，例如进行性肌肉无力和认知能力受损。我们过去的努力已经使用体内和体外衰老模型鉴定了氧化应激的蛋白质标记物，并表征了氧化和衰老对关键钙调节蛋白的影响。我们还进行了许多重要的观察，支持衰老组织中参与 Ca2+ 信号传导的蛋白质发生氧化修饰。在过去的几年里，整个研究事业发生了巨大的变化，这主要是由于人类基因组测序以及用于分析细胞和组织中发生的转录、翻译和信号事件的新技术的开发。因此，项目参与者用于研究衰老过程的策略已经发展到能够利用最新的研究进展。不过，整个研究工作的主题仍然是衰老过程中的氧化应激和 Ca2+ 调节。涉及蛋白质复合物的亚蛋白质组学研究、基因组学以及代谢应激和结构和功能恢复的转基因小鼠模型的新方法现已成为该计划研究的组成部分。该申请是计划项目续展的重新提交，由 3 个项目组成：项目 1，肌肉减少症和细胞凋亡：SERCA 和 Bcl-2 的作用；项目2，突触筏结构域和质膜Ca2+-ATP酶的年龄依赖性变化；项目 3，谷氨酸神经传递、衰老、长寿和神经突重塑。两个科学核心的活动已扩大，以提供实现项目目标所需的新服务和基本专业知识。核心 B 进行了扩展，包括对衰老组织的神经元膜进行详细的脂质分析，以及用于定量蛋白质变化的蛋白质同位素标记方法。核心 C 中添加了电子显微镜和定量成像。核心 A、B 和 C 均经过扩展，包括增强的数据共享、关系数据库和生物信息学分析工具，用于系统集成项目信息。该计划的短期目标是确定衰老过程中神经元和肌肉细胞的分子变化，这些变化会改变细胞内 Ca2+、代谢应激、氧化应激、细胞凋亡事件的启动和细胞恢复过程的控制。长期目标是表征导致老年人衰弱的两种病症——肌肉减少症（肌肉细胞损失/肌肉力量丧失）和选择性神经变性——所涉及的分子事件。希望定义产生这些衰老条件的分子和细胞过程可能会导致发现未来治疗干预的新靶点。