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

项目摘要 全球疾病负担，特别是老年人口的疾病负担，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 2018年，仅条件一项就导致超过85万美国人死亡。这些疾病是高度可遗传的， 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，经常被认为是一个标志 在人类和模式生物中的衰老和与年龄相关的疾病。尽管普遍存在关联，但严格的 线粒体功能障碍是否是年龄相关疾病的原因还有待评估。事实上, 唯一已知的由线粒体功能障碍引起的疾病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, 衰老和老年相关疾病中出现的线粒体功能障碍的原因尚不清楚。在这项研究中， 候选人的长期目标是研究导致线粒体功能障碍的机制 以及它与衰老和使用自然人类遗传变异的与年龄相关的常见病的因果联系。 目标1将系统地评估线粒体功能障碍与年龄相关疾病之间的联系 使用新的和现有的方法；AIM 2将测试线粒体功能障碍与年龄之间的因果关系- 使用一种新的线粒体功能障碍测量方法；AIM 3将评估 通过阐明和研究线粒体的遗传结构来读出线粒体功能障碍的机制。 总体而言，这项工作将首次全面分析机制和因果结构之间的联系 线粒体功能障碍对人类老年性疾病的影响。这一分析的结果有可能 发现衰老和常见的与年龄相关的疾病的新机制，可能为 以机制为基础的新疗法。 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 Neale，受益于线粒体生物学、年龄相关疾病方面的世界级专业知识和指导 生物学和统计遗传学，这是成功执行拟议工作所必需的。部分通过寻址 与衰老、线粒体生物学和统计遗传学领域相关的基本问题， 应聘者的培训计划将在书面和口头沟通、教学和 导师和临床护理。哈佛医学院高度协作的专家科学界 将成功地为候选人作为学术临床医生-科学家的职业生涯做好准备。

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.