FUNDC1介导的心肌细胞和血小板线粒体自噬在心脏缺血/复灌小鼠模型中的作用及其调控机制研究

FUNDC1 is a mitochondrial autophagy (mitophagy) receptor. Our latest study shows that there is an increase in the number of dysfunctional mitochondria of both platelets and cardiomyocytes in mice with Fundc1 deletion. We hypothesize that there is dysfunction of mitophagy in mice with Fundc1 deletion, which results in impaired cardiac dysfunctions. The relationship between FUNDC1-dependent mitophagy, ischemia/reperfusion (I/R) heart injury and cardiac functions of I/R mice models with Fundc1 specifically knockout in cardiomyocytes and platelets and myocardial infarction patients will be analyzed in this project to understand effect and molecular mechanism of FUNDC1-mediated mitophagy on both quantity and quality of mitochondria in cardiomyocytes and platelets, cellular activity, I/R heart injury and cardiac functions. Mice will be pre-treated with hypoxia (8%) or a membrane-permeable peptide with inhibition role on FUNDC1-mediated mitophagy to enhance or inhibit mitophagy, and then relationship between mitophagy and I/R heart injury and cardiac functions will be further explored. The polymorphism of Fundc1 in patients with myocardial infarction will be investigated to understand the correlation between Fundc1 polymorphism, mitophagy and degree of myocardial infarction. The present study will not only provide better basis for studying roles of mitophagy in both cardiomyocytes and platelets in coordination regulation of cardiac functions, but also may provide new theory evidence for the diagnosis and treatment of myocardial infarction.

FUNDC1是线粒体自噬的受体。我们最新的研究显示，Fundc1缺失小鼠的血小板和心肌细胞线粒体数目增加，功能异常。我们推测Fundc1缺失小鼠的线粒体自噬异常，并由此导致心脏功能异常。本研究采用Fundc1组织特异敲除小鼠心脏缺血/复灌（Ischemia/Reperfusion，I/R）模型和心肌梗死患者分析FUNDC1介导的线粒体自噬与I/R心脏损伤和功能的关系，了解线粒体自噬在心肌细胞和血小板线粒体数量和质量，细胞活性，I/R心脏损伤和功能中的机制。利用低氧或能抑制FUNDC1线粒体自噬的可穿膜肽预处理小鼠，再分析线粒体自噬与I/R心脏损伤的关系。分析心肌梗死患者Fundc1基因的多态性，了解Fundc1基因多态性与线粒体自噬，心肌梗死的关系。本研究将为FUNDC1在心肌细胞和血小板线粒体自噬协同调控心脏功能的研究提供良好的基础，并有可能为心肌梗死的诊断和治疗提供新的理论依据。

FUNDC1是线粒体自噬的受体。我们的研究显示，Fundc1缺失小鼠的线粒体数目增加，线粒体自噬异常，并由此导致心脏相关的疾病。本研究采用Fundc1组织特异敲除小鼠心脏缺血/复灌（Ischemia/Reperfusion，I/R）模型和心肌梗死患者分析FUNDC1介导的线粒体自噬与I/R心脏损伤和功能的关系，阐明了心肌细胞和血小板线粒体自噬调控心脏I/R损伤和心脏功能的分子机制；发现心肌细胞和血小板线粒体自噬调节线粒体数量和质量，提出低氧预处理（Hypoxic preconditioning）可能是一种新的心梗治疗方式；发现血小板 FUNDC1可能是临床心肌梗死的biomarker，FUNDC1 可能是相关疾病治疗的潜在靶点，为相关疾病的检测、预防和治疗提供了理论依据；建立了FUNDC1依赖的线粒体自噬的筛选体系，筛选出特异调控FUNDC1介导的线粒体自噬的小分子化合物；设计和合成的针对 FUNDC1 的 LIR 结构域的小分子多肽能提高血小板的体外保存时间，获批国家发明专利；发现临床心肌病/低血氧症患者 Fundc1 基因的多态性位点（18-Tyr，17-Ser 和 13-Ser 等），这些位点与疾病密切相关。本研究将为FUNDC1在心肌细胞和血小板线粒体自噬协同调控心脏功能的研究提供良好的基础，并有可能为心肌梗死的诊断和治疗提供新的理论依据。