再生医学蕴含着能完全修复心肌梗死损伤后心脏功能的希望。使用具有天然心脏再生能力的斑马鱼模型，我们发现了一组新的内源性nkx2.5+心脏祖细胞群，在心脏受损后发挥重要功能；初步结果显示，Notch信号可能通过新颖的机制调节再生和疤痕形成平衡，指导了nkx2.5+心脏祖细胞命运。本项目在此基础上，通过新的荧光报告子和可诱导的cre/loxp转基因系统，探究nkx2.5+心脏祖细胞在稳态和再生心脏中的活动规律；建立心脏损伤后内源性的nkx2.5+心脏祖细胞命运谱系。揭示Notch信号调变如何影响心脏的再生/疤痕；以及稳态和再生的心脏中Notch响应细胞的命运及心电传导改变。同时，通过小分子化合物筛选确认新的能够调控nkx2.5+细胞命运的通路并深入分析。本研究有望阐明新生心肌的细胞来源和基因调控，深入认识心脏再生修复机制，建立一种激发内源性的心脏再生潜能的新的治疗模式。

Regenerative medicine holds the promise of fully restoring cardiac function following Myocardial Infarctions. By using the zebrafish model that achieves innate cardiac regenerative capacity, we identified a small, endogenous nkx2.5+ cardiac progenitor cells (CPCs) population in the adult heart and found that they play a vital role in the injuried heart. Our preliminary studies show that Notch signaling may regulate the equilibrium of regeneration and scarring in a novel way so as to direct the fate of nkx2.5+CPCs. Building on our preliminary data, we propose to characterize the activity of nkx2.5+ CPCs during homeostasis and regeneration using new fluorescent reporters and inducible Cre/loxP lineage tracing systems. We also plan to determine the fate map of endogenous and post-injury nkx2.5+ CPCs to CM regeneration. In this study, we will determine how experimental decreases and increases in Notch signaling affect heart regeneration and scarring using inducible transgenic lines, and characterize and lineage trace Notch-responsive cells in homeostatic and regenerating hearts，as well as the change of cardiac electrophysiology. In the meantime, using small molecule screening, novel genetic programs orchestrating the nkx2.5+ CPCs fate will be uncovered and fully characterized. We anticipate that this study can illustrate the source and genetic regulation of newly produced cardiomyocytes, advance our fundamental understanding of heart repair and regenerative mechanisms, and potentially lead to new therapeutic strategies for treating heart disease.