The role of mitochondrial dysfunction in age-related disease: a human genetic approach

线粒体功能障碍在年龄相关疾病中的作用：人类遗传方法

• 批准号: 10477979
• 负责人: Rahul Gupta
• 金额: $ 3.97万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10477979
• 关键词: Address; Adult; Age; Aging; Agreement; American; Architecture; Biological Markers; Biology; Blood; Cardiovascular Diseases; Cell Respiration; Cells; Cessation of life; Chronic Disease; Communities; Complex; Coronary Arteriosclerosis; DNA; Data; Disease; Educational process of instructing; Elderly; Etiology; Fluorescence; Functional disorder; Genes; Genetic; Genetic Variation; Genotype; Goals; Heritability; Human; Human Genetics; Impairment; Individual; Inherited; Investigation; Laboratories; Lesion; Link; Literature; Measures; Mendelian randomization; Mentorship; Methods; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Mitochondrial Proteins; Modeling; Mus; Mutation; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Organelles; Oxidative Phosphorylation; Pathogenesis; Patients; Phenotype; Population; Predisposition; Production; Proteome; Publishing; Rare Diseases; Resources; Rest; Risk; Role; Sampling; Scientist; Somatic Mutation; Structure; Testing; Therapeutic; Training; Validation; Variant; Work; Writing; age related; aging population; biobank; burden of illness; career; clinical care; cohort; disorder risk; exome; genetic approach; genetic architecture; genome wide association study; genomic locus; insight; medical schools; metabolomics; mitochondrial DNA mutation; mitochondrial dysfunction; model organism; new therapeutic target; novel; novel marker; oral communication; rare variant; skills; statistics; trait; virtual

Project Summary The global disease burden, particularly in the elderly population, is dominated by age-related chronic diseases such as neurodegenerative disease, coronary artery disease, and type 2 diabetes; these three conditions alone accounted for over 850,000 American deaths in 2018. These conditions are highly heritable, however the specific mechanisms linking genetics to age-related disease pathogenesis remain unclear. Mitochondrial dysfunction, and more specifically, energy production impairment, is often invoked as a hallmark of aging and age-related disease in humans and in model organisms. Despite pervasive associations, a rigorous assessment of if mitochondrial dysfunction is causal for age-related diseases has yet to be performed. In fact, the only disorders truly known to be caused by mitochondrial dysfunction are inherited mitochondrial diseases, caused by genetic lesions in ~300 mitochondrial DNA- or nuclear DNA-encoded mitochondrial genes. In addition, the cause of the mitochondrial dysfunction seen in aging and age-related disease remains unclear. In this study, the candidate’s long-term goal is to investigate the mechanisms leading to mitochondrial dysfunction and its causal link with aging and age-related common disease using natural human genetic variation. AIM 1 will systematically assess the association between mitochondrial dysfunction and age-related disease using novel and existing methods; AIM 2 will test for causation between mitochondrial dysfunction and age- related disease using a novel measure of mitochondrial dysfunction; and AIM 3 will assess the genetic mechanism of a readout of mitochondrial dysfunction by elucidating and investigating its genetic architecture. Overall, this work will be the first comprehensive analysis of the mechanism and causal structure linking mitochondrial dysfunction to human age-related disease. The results of this analysis have the potential to uncover novel mechanisms underlying aging and common age-related diseases, potentially paving the way to novel mechanism-based therapeutics. This work will be completed jointly in the well-resourced laboratories of Drs. Vamsi Mootha and Benjamin Neale, benefiting from world-class expertise and mentorship in mitochondrial biology, age-related disease biology, and statistical genetics as required for successful execution of the proposed work. In part by addressing fundamental questions of relevance for the fields of aging, mitochondrial biology, and statistical genetics, the candidate’s training plan will additionally important skills in written and oral communication, teaching and mentorship, and clinical care. The highly collaborative expert scientific community at Harvard Medical School will successfully prepare the candidate for a career as an academic clinician-scientist.

项目摘要 全球疾病负担，特别是老年人的疾病负担，主要是与年龄有关的慢性疾病， 神经退行性疾病、冠状动脉疾病和2型糖尿病等疾病;这三种疾病 2018年，仅条件就造成了超过85万美国人死亡。这些疾病是高度遗传的， 然而，将遗传学与年龄相关疾病发病机制联系起来的具体机制仍不清楚。 线粒体功能障碍，更具体地说，能量产生障碍，通常被认为是一个标志性的疾病， 衰老和与年龄有关的疾病的研究。尽管普遍的协会，一个严格的 线粒体功能障碍是否是与年龄有关的疾病的原因尚待评估。事实上， 真正已知的由线粒体功能障碍引起的唯一病症是遗传性线粒体疾病， 由约300个线粒体DNA或核DNA编码的线粒体基因的遗传损伤引起。此外，本发明还提供了一种方法， 在衰老和与年龄相关的疾病中观察到的线粒体功能障碍的原因仍然不清楚。在本研究中， 候选人的长期目标是研究导致线粒体功能障碍的机制 以及它与衰老和与年龄有关的常见疾病的因果关系。 AIM 1将系统地评估线粒体功能障碍与年龄相关疾病之间的关联 使用新的和现有的方法; AIM 2将测试线粒体功能障碍和年龄之间的因果关系， 使用线粒体功能障碍的新措施来评估相关疾病; AIM 3将评估遗传性 通过阐明和研究其遗传结构来读出线粒体功能障碍的机制。 总的来说，本工作将首次全面分析机制与因果结构的联系 线粒体功能障碍与人类年龄相关疾病的关系。该分析的结果有可能 揭示衰老和常见年龄相关疾病的新机制，可能为 新的基于机制的疗法。 这项工作将在Vamsi Mootha博士和Benjamin博士资源充足的实验室共同完成 尼尔，受益于世界一流的专业知识和指导，在线粒体生物学，年龄相关疾病 生物学和统计遗传学，以成功执行拟议的工作。部分原因是 与衰老、线粒体生物学和统计遗传学领域相关的基本问题， 候选人的培训计划将额外的重要技能，在书面和口头沟通，教学和 指导和临床护理。哈佛医学院高度合作的专家科学界 将成功地准备候选人的职业生涯作为一个学术临床科学家。