Mitochondrial genetics in skeletal muscle aging

骨骼肌衰老中的线粒体遗传学

基本信息

批准号：
8520132
负责人：
Jonathan Wanagat
金额：
$ 9.67万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8520132
关键词：
Activities of Daily Living Address Age Aging Aging-Related Process American Area Atrophic Biochemical Biological Biology of Aging Cell Culture Techniques Cell Death Cell Respiration Cell Separation Cell physiology Code Complex Data Deletion Mutation Development Disease Electron Transport Etiology Event Excision Exhibits Exonuclease Fiber Flow Cytometry Functional disorder Funding Gene Targeting Generations Genetic Genetic Recombination Genetically Engineered Mouse Geriatrics Gerontology Goals Human In Situ Individual Intervention K-Series Research Career Programs Laboratories Life Light Link Measurement Mediating Mentors Mitochondria Mitochondrial DNA Modeling Mus Muscle Fibers Muscle function Mutant Strains Mice Mutation Phenotype Physical Function Physicians Physiological Play Polymerase Predisposition Public Health Research Research Personnel Resources Role Scientist Secondary to Series Shock Skeletal Muscle Specificity Techniques Testing Therapeutic Intervention Time Tissues Touch sensation Training Transgenic Mice Transgenic Organisms Universities Washington Work age related aged base career catalase frailty genetic manipulation in vivo laser capture microdissection mitochondrial DNA mutation mitochondrial dysfunction mitochondrial genome mouse model muscle aging muscle form muscle strength older patient oxidative damage prevent programs sarcopenia satellite cell selective expression skills

项目摘要

DESCRIPTION (provided by applicant): Sarcopenia, the age-related loss of muscle mass and strength, is a significant contributor to frailty and other declines of aging. Many etiologies have been implicated and there is growing evidence that mitochondria and the mitochondrial genome may play a central role. Recent studies suggest a series of events linking oxidative damage to mitochondrial mutations, mitochondrial dysfunction, fiber atrophy and loss. The studies in the current proposal test the correlations observed in earlier work through the genetic manipulation of mitochondrial mutation rate. Our preliminary data show that the mitochondrial targeting of catalase and exonuclease-deficient polymerase gamma mutant mice are important models of decreased and increased mitochondrial mutation rate, respectively. These models will test the causality of mitochondrial mutations in the aging process and pinpoint areas amenable to intervention. My goal is to become an independent investigator studying basic mechanisms of aging and develop disease-modifying therapies that will benefit my older patients. During the proposed funding period, I will acquire new skills in the areas of mouse genetics, husbandry and colony management, satellite cell isolation and culture, and the measurement of mitochondrial function by flow cytometry. These techniques take full advantage of the resources available at the University of Washington, including the Nathan Shock Center of Excellence in the Biology of Aging and the Transgenic Resource Laboratory, in addition to the internationally-recognized expertise of my mentors and collaborators. Specific Aim 1: Test the hypothesis that systemic decreases in oxidative damage will decrease age-associated mitochondrial genetic and enzymatic abnormalities and ameliorate sarcopenia. Specific Aim 2: Test the hypothesis that systemic increases in mtDNA mutations will increase age- associated mitochondrial genetic and enzymatic abnormalities and worsen sarcopenia. Specific Aim 3: Using a conditional mitochondrial mutator mouse, I will test the susceptibility of skeletal muscle to selective expression of the mtDNA mutator phenotype and establish the relationship between occurrence and biological impact of mtDNA deletion mutations. RELEVANCE: The proposed studies will uncover the basic changes that occur with aging in skeletal muscle which are major contributors to frailty. Elucidating the basic mechanisms of muscle aging will suggest points for therapeutic intervention to prevent this age-related decline. Additionally, this Career Development Award will support the unique career of a physician-scientist working in the areas of gerontology and geriatric medicine, for which there is a growing public health need.

描述（由申请人提供）：与年龄相关的肌肉质量和力量损失的肌肉减少症是脆弱和其他衰老下降的重要贡献者。许多病因已被牵涉到许多病因，越来越多的证据表明线粒体和线粒体基因组可能起着核心作用。最近的研究表明，将氧化损伤与线粒体突变，线粒体功能障碍，纤维萎缩和损失联系起来的一系列事件。当前建议中的研究测试了通过线粒体突变率的基因操纵在早期工作中观察到的相关性。我们的初步数据表明，过氧化酶和外核酸酶缺陷的聚合酶伽马突变小鼠的线粒体靶向分别是降低和增加线粒体突变率的重要模型。这些模型将在老化过程中测试线粒体突变的因果关系，并确定可根据干预的区域。我的目标是成为研究衰老的基本机制的独立研究者，并开发改良疾病的疗法，从而使我的老年患者受益。在拟议的资金期间，我将在小鼠遗传学，饲养和菌落管理，卫星细胞隔离和培养以及通过流式细胞仪测量线粒体功能方面获得新技能。这些技术充分利用了华盛顿大学可用的资源，包括内森冲击卓越的衰老生物学和转基因资源实验室，以及我的导师和合作者的国际认可的专业知识。具体目的1：检验氧化损伤系统性降低的假设将减少与年龄相关的线粒体遗传和酶促异常和改善肌肉减少症。具体目的2：检验以下假设：mtDNA突变的全身性增加将增加与年龄相关的线粒体遗传和酶促异常，并使肌肉减少症恶化。特定目标3：使用条件线粒体突变器小鼠，我将测试骨骼肌对MTDNA突变器表型选择性表达的敏感性，并建立MTDNA缺失突变的发生与生物学影响之间的关系。相关性：拟议的研究将发现骨骼肌衰老的基本变化，这是造成脆弱的主要因素。阐明肌肉衰老的基本机制将提出治疗干预的观点，以防止与年龄相关的下降。此外，该职业发展奖将支持在老年医学和老年医学领域工作的医师科学家的独特职业，为此，公共卫生的需求日益增长。