本项目对应指南重点资助研究方向第三点“组织器官再生与结构功能重构障碍的机制”。心肌梗死高发于老年群体，目前尚无有效治疗手段实现受损心肌的再生修复。心肌细胞直接重编程技术旨在有效转化成纤维细胞为诱导型功能性心肌细胞（iCM），有望解决该医学难题。申请人前期构建了高效的心肌直接重编程体系，并对重编程过程中细胞命运转化轨迹及分子机制做了初步探究。本项目初步研究发现，衰老个体来源的成纤维细胞直接重编程为iCM的效率比新生成纤维细胞低5-10倍，且iCM功能不完善。前期单细胞多组学研究表明，衰老导致心脏成纤维细胞异质性增加等变化。本项目旨在系统阐释衰老导致心脏再生修复障碍的调控机理。将在单细胞水平系统研究衰老导致心脏成纤维细胞基因转录和表观遗传改变，揭示其抑制iCM重编程的分子机制，并靶向衰老相关核心因子以提高iCM直接重编程效率。项目的实施将为推动心肌直接重编程策略修复心脏的临床转化打下基础。

This research aims at dissecting the molecular barriers for heart regeneration by direct reprograming. Myocardial infarction related progressive heart failure is one of the major cause for global morbidity and mortality. Current therapeutic approaches have limited capacities to regenerate the injured myocardium. Direct cardiac reprograming that convert scar-forming fibroblasts into induced cardiomyocytes (iCMs) offers great opportunity for heart repair. Our preliminary results have demonstrated that aging inhibits iCM reprogramming by 5-10 folds, which is related with increased heterogeneity of cardiac fibroblast with aging. Our research will explore the dynamic alternations of transcriptomic and epigenomic landscapes of cardiac fibroblasts at single cell level during aging, illustrate the molecular mechanism of how aging suppresses iCM reprogramming, and further identify and target key aging-related molecules to enhance iCM conversion in vitro and in vivo. Our study will provide new insights into heart regeneration by direct reprograming.