迷走刺激及拟胆碱药防治缺血性心脏病的线粒体质量控制研究

缺血性心脏病（IHD）是危害人类健康的首要疾病，线粒体质量控制（MQC）对维持生命活动具有重大意义，目前尚未有MQC与IHD防治的系统研究。前期实验发现改善迷走可减轻心血管缺血损伤，本项目将建立IHD模型结合迷走刺激或拟胆碱药干预，1. 探讨改善迷走对MQC（线粒体分裂/融合及受损线粒体识别/清除）的影响；2. 阐明迷走调节对MQC细胞器间交互调节机制。a:应用超微结构分析和免疫共沉淀等技术探讨迷走神经对Grp75/VDAC1/IP3R1复合体的作用，明确线粒体与内质网交互调节钙稳态介导MQC的药物靶点；b:应用siRNA和激光共聚焦等技术探讨迷走神经对线粒体未折叠蛋白反应（线粒体基质/膜间隙UPRmt）及蛋白转位的影响，明确线粒体与细胞核交互调节线粒体蛋白稳态的信号通路。本研究将有助于阐明改善迷走调节MQC启动内源性心血管保护的分子机制，寻求MQC的药理学干预措施和线粒体靶向抗缺血药物的开发。

Ischemia heart disease (IHD) is the life-threatening cardiovascular disease. Mitochondrial quality control (MQC) is of great significance for the maintenance of life activities. There is not yet systematic study about link of MQC and IHD. Our previous studies have suggested that improved vagal activity ameliorates myocardial and vascular ischemic injury. This project will establish IHD models combined with vagal stimulation and cholinergic drug intervention: ① investigate the effect of improving vagal activity on MQC (mitochondrial fission/ fusion and impaired mitochondrial elimination); ② disclose the molecular mechanisms of vagal nerve regulation of inter-organelle communication. a: explore the effects of improved vagal activity on Grp75/VDAC1/IP3R1 complex to clarify the mitochondria/ endoplasmic reticulum calcium crosstalk identified as drug target of MQC applying electron microscopy and co-immunoprecipitation; b: explore the effects of vagal nerve on mitochondrial unfolded protein response (UPRmt in the mitochondrial matrix and in the intermembrane space) to determine the signal pathway of the communication between mitochondria and nucleus which mediates mitochondrial protein homeostasis using siRNA and laser confocal microscopy. Our research aims to clarify the molecular mechanism underlying improving vagal nerve exerts cardiovascular effects through regulating MQC, explore pharmacological interventions of MQC and novel mitochondrial targeting anti-ischemic drugs.