肌纤形成调节因子-1改善线粒体功能调控缺血心肌代谢重塑的机制

心肌代谢重塑是调控肥大心肌转向衰竭的新机制，MR-1是新发现的心肌肥大相关分子，前期证实其具有激酶活性并调节心肌重塑。本项目提出“MR-1作为新蛋白激酶通过磷酸化Drp1调节线粒体分裂、增加新生线粒体数量，通过磷酸化ERK1/2抑制线粒体mPTP过度开放、维持成熟线粒体功能；从而改善心肌能量代谢重塑，延缓代偿性重塑心肌转向衰竭的进程，是调控重塑心肌线粒体功能、影响重塑心肌转向衰竭的关键分子”的科学假说。在证实干预MR-1影响缺血后心肌重塑的基础上，研究MR-1自身磷酸化激活的机制，证实MR-1通过自身磷酸化激活的关键环节；进一步研究MR-1调节线粒体功能的机制，证实MR-1通过磷酸化Drp1调节线粒体分裂、通过磷酸化ERK1/2抑制线粒体mPTP过度开放，维持线粒体功能，改善心肌能量代谢重塑。从整合调控代谢重塑的角度为肥大心肌转向衰竭的机制研究提供新思路，为心力衰竭的防治提供新药研发靶点。

Myocardial metabolic remodeling is a new mechanism by which hypertrophied myocardium develops toward heart failure. Myofibrillogenesis regulator 1(MR-1) is a newly discovered molecule involved in myocardial hypertrophy. Our previous researches and other reports demonstrate that MR-1 has kinase activity and regulates myocardial remodeling. Therefore, we put forward the following hypothesis that MR-1 is the key molecule mediating the development of hypertrophied myocardium toward heart failure through integrated regulation of metabolic remodeling. It increases mitochondria fission by phosphorylating Drp1 and inhibits mPTP opening by phosphorylating ERK1/2, thereby improving myocardial metabolic remodeling and delaying progress from myocardial hypertrophy to heart failure. Based on the effects of MR-1 on myocardial remodeling induced by ischemia, we shall investigate the auto-phosphorylation mechanism and its key link of MR-1. Furthermore, the mechanisms underlying the regulatory effects of MR1 on mitochondrial function will be elucidated to prove that MR1 ameliorates mitochondrial function and improves myocardial metabolic remodeling by Drp1-phosphorylation-mediated mitochondria fission and by ERK1/2-phosphorylation-mediated inhibition of mPTP opening. The results of this project may provide new thought for further studying the molecular mechanisms by which hypertrophied myocardium develops toward heart failure. Also, it may provide targets of new drug development for the prevention and treatment of heart failure.