冠心病相关线粒体tRNAThr 15927G>A突变的致病机制研究

冠心病是一种复杂性疾病，由遗传因素、环境因素或两者相互作用所致。在冠心病发生的诸多危险因素中，遗传因素起着十分重要的作用。我们在前期工作中发现一个呈母系遗传特征的冠心病家系，并发现此家系中线粒体tRNAThr 15927G>A突变是冠心病的致病因素之一。本项目拟在此基础上构建转线粒体人脐带静脉内皮细胞系，检测相同核基因背景下线粒体tRNAThr 15927G>A突变对人脐带静脉内皮细胞线粒体功能和细胞功能的影响。诱导携带线粒体tRNAThr 15927G>A突变的冠心病患者特异性iPSCs，并将其定向分化为血管内皮细胞。评估该突变对iPSCs诱导过程及iPSCs干性的影响，检测该突变对血管内皮细胞线粒体功能和细胞功能的影响，从分子和细胞层面探讨冠心病线粒体tRNAThr 15927G>A突变在冠心病病理过程中的作用，为冠心病的致病机制和治疗方法研究提供新的视角。

Coronary heart disease is a complex disease caused by multi-factors including environment and inherited risk factors. Our previous studies identified the mitochondrial tRNAThr 15927G>A mutation associate with coronary heart disease. To further understand the pathophysiology of maternally transmitted coronary heart disease, we will construct cybrids by the fusion of R6G-treated human umbilical cord vein epithelial cells and enucleated lymphocyte cells carrying mitochondrial tRNAThr 15927G>A mutation, examine the mitochondria and cell dysfunctions caused by this mutation in the same nuclear genetic context. Coronary heart disease patient specific iPSCs will be generated from lymphoblastoid cell lines, and subsequently directed to differentiate into vascular endothelial cell. Then, we will examine the effects of mitochondrial tRNAThr 15927G>A mutation on the process of iPSCs induction, characteristics of iPSCs and the function of mitochondria. Thus, the success of this project will help to understand the pathogenesis of mitochondrial tRNAThr 15927G>A mutation related coronary heart disease, provide new perspectives for the research of coronary heart disease pathology and therapy.