Reactive Oxygen Species and Aging

活性氧与老化

基本信息

批准号：
8234023
负责人：
ELIAS K MICHAELIS
金额：
$ 146.14万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-08-15 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8234023
关键词：
Aging Aging-Related Process Apoptosis Apoptotic Bioinformatics Ca(2+)-Transporting ATPase Cell membrane Cell physiology Cells Cognitive Disease Electron Microscopy Event Future Genomics Glutamates Human Development Human Genome Image Label Lead Lipids Longevity Membrane Metabolic stress Methods Modification Molecular Molecular Genetics Muscle Cells Muscle Weakness Nerve Degeneration Neurites Neurons Oxidative Stress Participant Performance Process Proteins Proteomics Reactive Oxygen Species Recovery Regulation Research Role Services Signal Transduction Structure Synapses Therapeutic Intervention Tissues Transgenic Mice age related aged analytical tool data sharing in vitro Model in vivo mouse model muscle strength neurotransmission new technology novel strategies oxidation programs protein complex relational database sarcopenia

项目摘要

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大大扩展了我们对有助于长寿和与年龄相关疾病的基本过程的理解。该程序的主要重点是因为它的成立是这样的断言，即年龄依赖性增加氧化应激和细胞Ca2+汉型的变化，以产生几种众所周知的衰老表现，例如渐进的肌肉无力和损害认知能力。我们过去的努力导致了氧化应激的蛋白质标志物的鉴定，并使用体内和体外衰老模型均使用氧化和衰老对临界Ca调节蛋白的影响。我们还做出了许多重要的观察结果，以支持对衰老组织中Ca2+信号传导的蛋白质进行氧化修饰的发生。在过去的几年中，总体研究企业中发生了巨大的转变，这主要是由于人类基因组的测序以及新技术的开发，用于分析细胞和组织中发生的转录，翻译和信号事件。结果，计划参与者用于研究衰老过程的策略已经发展为利用最新的研究进展。但是，整体研究工作的主要主题仍然是衰老中的氧化应激和Ca2+调节。涉及蛋白质复合物，基因组学和转基因小鼠模型的代谢压力和结构和功能的转基因小鼠模型的新方法现在是该程序研究的组成部分。该申请是重新提交该计划项目的重新提交，由3个项目组成：项目1，肌肉减少症和凋亡：SERCA和BCL-2的作用；项目2，突触筏结构域和质膜Ca2+-ATPase的年龄依赖性变化；项目3，谷氨酸神经传递，衰老，寿命和神经突重塑。这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。扩展了核心B，包括来自衰老组织的神经元膜和蛋白质同位素标记方法的详细脂质分析，用于定量蛋白质变化。将电子显微镜和定量成像添加到CoreC。CoreA，B和C均扩展到包括增强的数据共享，关系数据库和生物信息学位分析工具，以系统地集成项目中的信息。该程序的短期目标是在衰老过程中定义神经元和肌肉细胞的分子变化，从而改变了对细胞内Ca2+的控制改变，代谢应激，氧化应激，凋亡事件的启动以及细胞恢复过程。长期目标是表征与诱导两种衰老的肌肉减少症（肌肉细胞损失/肌肉力量丧失/肌肉力量）和选择性神经变性的分子事件。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措施的新靶标。

项目成果

期刊论文数量（163）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metal-catalyzed oxidation of histidine in human growth hormone. Mechanism, isotope effects, and inhibition by a mild denaturing alcohol.

人类生长激素中组氨酸的金属催化氧化。

DOI：
10.1074/jbc.272.14.9019
发表时间：
1997
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Zhao,F;Ghezzo-Schöneich,E;Aced,GI;Hong,J;Milby,T;Schöneich,C
通讯作者：
Schöneich,C

Metal-catalyzed oxidation of brain-derived neurotrophic factor (BDNF): analytical challenges for the identification of modified sites.

脑源性神经营养因子 (BDNF) 的金属催化氧化：识别修饰位点的分析挑战。

DOI：
10.1023/a:1007569431038
发表时间：
2000
期刊：
Pharmaceutical research
影响因子：
3.7
作者：
Jensen,JL;Kolvenbach,C;Roy,S;Schöneich,C
通讯作者：
Schöneich,C

Oxidative inactivation of purified plasma membrane Ca2+-ATPase by hydrogen peroxide and protection by calmodulin.

过氧化氢对纯化质膜 Ca2-ATP 酶的氧化失活和钙调蛋白的保护。

DOI：
10.1021/bi034565u
发表时间：
2003
期刊：
Biochemistry.
影响因子：
0
作者：
Zaidi,Asma;Barron,Lorena;Sharov,VictorS;Schoneich,Christian;Michaelis,EliasK;Michaelis,MaryL
通讯作者：
Michaelis,MaryL

Redox properties of Met(35) in neurotoxic beta-amyloid peptide. A molecular modeling study.

神经毒性 β-淀粉样肽中 Met(35) 的氧化还原特性。