Somatic mtDNA mutations in brain aging: a single-cell approach

大脑衰老中的体细胞 mtDNA 突变：单细胞方法

• 批准号: 7819316
• 负责人: Konstantin Khrapko
• 金额: $ 36.89万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7819316
• 关键词: Aging; Aging-Related Process; Brain; Cells; DNA; Defect; Disease; Excision; Funding; Generations; Goals; Human; Inherited; Metabolism; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Molecular; Muscle; Mutation; Neurons; Oxidative Stress; Parents; Pigments; Play; Positioning Attribute; Process; Recovery; Research; Role; Sampling; Societies; Source; Substantia nigra structure; Technology; Testing; Tissues; United States National Institutes of Health; Work; age related; aging brain; brain tissue; cell type; mitochondrial DNA mutation; mitochondrial genome; oxidative DNA damage; parent grant; public health relevance; response

DESCRIPTION (provided by applicant): This is a request competitive revision of the parent grant R01 AG019787 in response to Notice Number (NOT-OD-09-058): NIH Announces the Availability of Recovery Act Funds for Competitive Revision. The goal of the parent application is to study mechanisms responsible for age-related degenerative processes and in particular, to test the hypothesis that mutations in mitochondrial DNA (mtDNA) are involved in the aging process, especially in brain aging. The parent proposal is particularly focused on mtDNA deletions, i.e. mutations resulting from removal of large DNA segments from the mitochondrial genome. These mutations are involved in a number of inherited degenerative mitochondrial diseases and have been hypothesized to play a role in the aging of brain, muscle and potentially other tissues. The processes that result in the generation of deletions in mtDNA are subject to intense research, but remain a matter of debate. A limitation of the parent grant is the lack of studies of the sources of mtDNA mutations. Work encompassed by the parent grant permitted to build several so-called mutational profiles of mtDNA deletions, i.e. the distributions of the positions of the deleted segments along the mitochondrial genome. This work hinted that mutational profiles of mtDNA deletions differ between different types of samples, which imply that deletions in different types of samples may be generated by different mechanisms. This revision will pursue two specific aims. First, the technology necessary for efficient studies of mutational profiles will be developed and used to confirm the preliminary finding of the differences among mutational profiles. Second, comparison of mutational profiles of aged brain tissue with profiles of a panel of samples that carry specific defects in mtDNA metabolism, mitochondrial dynamics or are subjected to oxidative stress will be used to test various hypotheses regarding the sources of mtDNA deletions in human aging and disease. PUBLIC HEALTH RELEVANCE: Aging and aging of the brain in particular imposes increasing burden on the society, however, molecular mechanisms leading to deteriorative changes in the brain are poorly understood. This revision seeks to determine the sources of deletions in mitochondrial DNA that are increasingly implicated in the aging process.

说明（由申请人提供）：这是对母基金 R01 AG019787 的竞争性修订请求，以响应通知编号 (NOT-OD-09-058)：NIH 宣布恢复法案资金可用于竞争性修订。母申请的目标是研究与年龄相关的退行性过程的机制，特别是检验线粒体 DNA (mtDNA) 突变与衰老过程（尤其是大脑衰老）有关的假设。母提案特别关注 mtDNA 删除，即从线粒体基因组中删除大 DNA 片段而产生的突变。这些突变与许多遗传性退行性线粒体疾病有关，并被假设在大脑、肌肉和其他潜在组织的衰老中发挥作用。导致线粒体 DNA 缺失产生的过程正在进行大量研究，但仍然存在争议。家长资助的一个限制是缺乏对 mtDNA 突变来源的研究。父母资助所涵盖的工作允许建立几个所谓的 mtDNA 删除的突变图谱，即删除片段沿线粒体基因组的位置分布。这项工作暗示，不同类型样本之间mtDNA缺失的突变谱不同，这意味着不同类型样本中的缺失可能是由不同的机制产生的。此次修订将追求两个具体目标。首先，将开发并使用有效研究突变谱所需的技术来确认突变谱之间差异的初步发现。其次，将衰老脑组织的突变谱与 mtDNA 代谢、线粒体动力学特定缺陷或遭受氧化应激的一组样本的谱进行比较，将用于测试有关人类衰老和疾病中 mtDNA 缺失来源的各种假设。 公共卫生相关性：老龄化和大脑老化给社会带来了越来越大的负担，然而，导致大脑恶化变化的分子机制却知之甚少。此次修订旨在确定线粒体 DNA 缺失的来源，这些缺失与衰老过程越来越相关。