线粒体tRNA ACC-stem突变在母系遗传性高血压发病中的功能及机制研究

高血压是心血管疾病最重要的危险因素之一。本研究在前期基础上，通过IPS技术构建人携带线粒体tRNAIleACC-stem 4263A to G位点突变的血管平滑肌细胞和内皮细胞，研究突变对tRNA剪切、结构和代谢影响；研究该突变对线粒体氧化应激、线粒体钙调节和能量代谢作用。通过过表达/抑制TRMT10C基因（RNase P酶蛋白亚基）调节tRNA剪切，分析tRNA合成、结构和代谢改变，对血管平滑肌细胞和内皮细胞氧化应激、增殖凋亡及共培养细胞系新生血管合成的影响。并进一步构建血管平滑肌和血管内皮组织特异性cre局部基因敲除小鼠模型，从整体、细胞、分子水平揭示线粒体tRNAIleACC-stem突变对血管平滑肌和血管内皮细胞线粒体结构及功能的影响，探讨线粒体tRNAIleACC-stem突变在促进血压升高和血管重构中的分子机制，为母系遗传高血压发病机制及寻找新的干预治疗靶点提供理论依据。

Hypertension is one of the most important risk factors for cardiovascular disease. Based on previous research work, we study on tRNA cleavage, structure and function of vascular smooth muscle cell and endothelial cell cybrids carrying mitochondrial tRNAIle ACC-stem 4263 A to G mutation by IPS technology. The effect of this mutation on mitochondrial oxidative stress, cellular calcium regulation, and energy metabolism will be evaluated. By over-expressing or siRNA TRMT10C, RNase P enzyme subunit, compare tRNA cleavage, structural and metabolic changes, and evaluate mitochondrial oxidative stress, cell proliferation and apoptosis, and neovascularization in co-cultured cell lines. To construct mice model of conditional gene knockout mediated by Cre system. To study on the effect of mitochondria tRNAIleACC-stem mutation on mitochondrial structure and function of vascular smooth muscle cell endothelium cell from whole animal experiments, cellular and molecular level. And to elucidate the mechanism of tRNA ACC-stem mutation in promoting high blood pressure and vascular remodeling, and provide theoretical basis for new therapeutic targets.