Biological Aging Mitrochondrial Variants and Coronary Artery Disease

描述（由申请人提供）：这项受指导的研究科学家职业发展奖（KOI）提案是一项为期四年的计划，旨在使候选人能够发展成为人类年龄相关疾病，特别是心血管疾病（CVD）遗传流行病学领域的独立研究者。该候选人在统计遗传学领域非常成功。然而，她缺乏流行病学、衰老生物学和临床心脏病学方面的正规培训，而这三个方面是人类慢性疾病领域杰出遗传流行病学家的关键组成部分。这笔赠款为广泛发展流行病学、心血管医学和衰老机制方面的技能提供了独特的机会。这些短期职业目标将通过正式课程、协作环境中的广泛指导以及研究计划的实施来实现，该研究计划将构成旨在调查线粒体基因多态性在生物衰老和心血管疾病中的作用的更大规模研究的基础。该候选人目前正在接受临床研究理学硕士 (MSCR-KL2) 计划，该计划为她提供为期一年的流行病学研究设计、混杂、临床数据库管理和慢性病流行病学方面的教学培训。在该 KOI 的第一年，她将继续接受临床试验、流行病学数据分析、拨款写作、CVD 生物学和衰老以及临床心脏病学方面的正式培训。这项教学培训将得到拟议的研究项目的补充，该项目首次提出线粒体相关的遗传变异是血管衰老、冠状动脉疾病（CAD）和主要不良心脏事件之间生物联系的基础。该项目将利用在她两位导师的指导下编制和维护的大型特征明确的冠状动脉造影患者队列（1,000 名患有严重 CAD 的患者和 1,000 名匹配的对照）。具体目标是 1) 检查线粒体相关变异是否与通过端粒长度测量的生物衰老有关； 2) 确定线粒体相关多态性是否与 CAD 和主要不良心脏事件相关。该 K0I 奖项将显着促进候选人成长和成熟，成为人类衰老疾病（特别是心血管疾病）领域的独立遗传流行病学家。 相关性：冠状动脉疾病（CAD）是一种典型的衰老疾病，是全世界死亡和残疾的主要原因。确定生物衰老和 CAD 之间的联系不仅将为衰老和 CAD 的病理生理学提供新的见解，而且还可能确定衰老和动脉粥样硬化形成的新生物标志物，最终可能改善多种与年龄相关的疾病的预测、预防和治疗。

DESCRIPTION (provided by applicant): This mentored research scientist career development award (KOI) proposal is a four-year plan to enable the candidate to develop into an independent investigator in the field of genetic epidemiology for human age-related disorders, in particular cardiovascular disease (CVD). The candidate has been very successful in the area of statistical genetics. However, she lacks formal training in epidemiology, aging biology and clinical cardiology, three crucial components for an outstanding genetic epidemiologist in human chronic disorders. This grant provides a unique opportunity for extensive development of skills in epidemiology, cardiovascular medicine and aging mechanism. These short term career goals will be accomplished through formal course work, extensive mentorship in a collaborative environment, and implementation of a research plan that will form the basis of a larger study aimed at investigating the role of mitochondrial gene polymorphisms in biological aging and CVD. The candidate is currently covered under a Master of Science in Clinical Research (MSCR-KL2) Program which provides her one year didactic training in epidemiological study design, confounding, clinical database management, and chronic disease epidemiology. During the first year of this KOI, she will continue formal training in clinical trials, epidemiological data analysis, grant writing, biology of CVD and aging as well as clinical cardiology. This didactic training will be complemented by the proposed research project, which proposes for the first time that mitochondrial-related genetic variants underlie the biological links among vascular aging, coronary artery disease (CAD) and major adverse cardiac events. This project will take advantage of a large well- characterized patient cohort for coronary angiography (1,000 patients with significant CAD and 1,000 matched controls) that has been compiled and maintained under the direction of her two mentors. The specific aims are 1) To examine whether mitochondrial-related variants are implicated in biological aging measured by telomere length; and 2) To determine whether mitochondrial-related polymorphisms are associated with CAD and major adverse cardiac events. This K0I award will significantly enhance the candidate's growth and maturation into an independent genetic epidemiologist in human aging disorders, in particular cardiovascular disease. RELEVANCE: Coronary artery disease (CAD), a typical aging disorder, is the leading cause of death and disability worldwide. Identification of the link between biological aging and CAD will not only provide novel insights into the pathophysiology of aging and CAD, but may also identify new biomarkers for aging and atherogenesis, which may, ultimately, improve prediction, prevention and treatment of a wide range of age-related disorders.