Mfn2调控内质网——线粒体钙离子转运参与心肌细胞程序性坏死的分子机制研究

心血管疾病严重威胁人类健康，心肌细胞死亡是许多心脏疾病发病的细胞学基础，研究心肌细胞死亡调控机制对于揭示心脏疾病的发病机制、提出新的防治策略具有重要意义。近年来研究发现心肌细胞程序性坏死参与心肌梗死等心脏疾病的发生。内质网中的钙离子通过内质网——线粒体钙离子转运促进线粒体钙离子超载，是引起心肌细胞程序性坏死的重要原因。有报道Mfn2具有促进内质网钙离子向线粒体转移的功能，我们前期研究发现Mfn2具有促进心肌细胞程序性坏死中的作用。在此研究基础上本项目将深入探讨Mfn2是否通过调控内质网钙离子的转运促进线粒体钙离子超载，参与心肌细胞程序性坏死；揭示Mfn2是否依赖于RIPK1/RIPK3参与心肌细胞程序性坏死的发生；在整体动物水平揭示Mfn2在心肌梗死中的作用及机制。这些研究结果将阐明心肌细胞程序性坏死的调控机制，为心脏疾病的防治提供理论依据和药物靶点。

Cardiovascular disease seriously threatens human health. Cardiomyocyte death is the cytological basis of many heart diseases. Therefore, it is important to investigate the regulation mechanism of cardiomyocyte death for revealing the pathogenesis of heart diseases and providing new strategies of prevention and treatment. Current studies show that programmed necrosis of cardiomyocyte involves in the occurrence of heart diseases such as myocardial infarction. Calcium ions promote mitochondrial calcium overload through the transport of calcium ion between endoplasmic reticulum-mitochondria, which is an important cause of programmed necrosis of cardiomyocytes. It has been reported that Mfn2 can promote the transfer of calcium ions from endoplasmic reticulum to mitochondria. Our previous study found that Mfn2 can promote the programmed necrosis of cardiomyocytes. Based on our previous work, this project will further explore whether Mfn2 promotes mitochondrial calcium overload and participates in programmed necrosis of myocardial cells through regulating the transport of endoplasmic reticulum calcium ions, reveal whether Mfn2 depends on RIPK1/RIPK3 to participate in the occurrence of programmed necrosis of cardiomyocytes, and investigate the role and mechanism of Mfn2 in myocardial infarction at the overall animal level. These findings will elucidate the regulatory mechanism of programmed necrosis of cardiomyocytes and provide theoretical basis and drug targets for the prevention and treatment of heart diseases.