Beclin1介导的非自噬通路调控心肌细胞重编程的作用及机制研究

心肌梗死及其所致的心力衰竭是全球主要的致病致死因素之一。目前尚无有效临床治疗手段实现心肌再生和心功能恢复。心肌细胞直接重编程技术能转化梗死区成纤维细胞为功能性心肌细胞（iCM），有望解决该医学难题。但重编程机制尚需深入研究，重编程效率有待进一步提高。本项目基于前期单细胞组学研究，经功能性筛选并进一步鉴定，发现敲低Beclin1促进iCM线粒体生成和重编程。初步研究发现Beclin1以不依赖于自噬的方式抑制经典Wnt/β-Catenin通路。但是，Beclin1-Wnt信号轴对iCM线粒体生成和重编程的确切作用有待进一步明确，其作用靶点和分子机制有待解析。本项目将系统研究Beclin1/Wnt信号通路在调控线粒体重构和iCM重编程中的分子机制和信号网络，并解析Beclin1介导的重编程通路对心肌再生的核心调控作用，为开发心梗心衰等心脏病治疗的新策略提供靶点及实验依据。

Loss of cardiomyocytes resulted from myocardial infarction or the progressive heart failure is the major cause of morbidity and mortality. Current therapeutic approaches have limited capacities to regenerate the injured myocardium. Cardiac reprogramming that directly converts fibroblasts into contractile iCMs (induced cardiomyocytes) offers a promising approach for heart repair yet much efforts are needed to fully depict the underlying molecular mechanisms and to improve the reprogramming efficiency. We performed loss of function screen with candidates from our previous single cell RNA sequencing that target mitochondrial and cellular metabolism, and we identified autophagic factor Beclin1 potentially regulates mitochondrial biogenesis and iCM reprogramming. Unexpectedly, Beclin1 was found to suppress iCM induction in an autophagy independent manner but inhibit activation of Wnt/β-Catenin signaling pathway. To thoroughly illustrate the mechanism(s) of Beclin1 mediated cell fate shaping of iCMs, this project aims to further depict the mitochondria remodeling and metabolic reconstruction affected by Beclin1, to identify direct targets of Beclin1-Wnt/β-Catenin signaling cascade and to identify the role of Beclin1 mediated in vivo reprogramming for heart repair.