哺乳动物出生后因心肌细胞（CM）停止增殖迅速丧失了心脏再生能力。这一过程伴随着剧烈的糖脂代谢重塑，然而与之相关的调控机制仍知之甚少。申报人前期研究发现：鞘磷脂代谢通路基因表达在心脏发育中发生显著变化。然而核心科学问题：鞘磷脂代谢是否调控CM增殖和心脏再生？仍未阐明。进一步研究发现该通路关键调节酶鞘氨醇激酶2（SphK2）及其代谢物S1P水平在心脏再生关键期显著上升；SphK2敲除小鼠CM增殖明显下降并完全丧失了心脏再生能力，而AAV9介导的SphK2过表达则显著促进了成年小鼠CM增殖和心梗修复；RNA-seq分析提示E2F家族可能是其下游靶点。本项目拟利用代谢组学和转录组学数据解析鞘磷脂代谢通路在心脏再生过程中的动态变化规律，通过基因操作、微量组织ChIP-seq和单细胞多组学测序等技术阐明SphK2/S1P调控CM增殖的下游基因和机制，为开发心梗修复的代谢干预新策略提供理论依据和靶点。

The neonatal mammalian heart is capable of regeneration for a brief window of time. However, they experience dramatic changes in the oxygen environment after birth, consequently resulting in cardiomyocyte (CM) quit proliferation and inability to regenerate. The rapid loss of cardiac regeneration capacity is coinciding with a postnatal shift of energy metabolism from anaerobic glycolysis to mitochondrial oxidative phosphorylation, particularly towards fatty-acid utilization. Thus, cardiac mitochondria produce elevated rates of reactive oxygen species when utilizing fatty acids, resulting in CM cell-cycle arrest through induction of DNA damage. However, whether other metabolism shift after birth would contribute to heart regeneration remained largely unknown..Our previous study found that the expression of most sphingomyelin metabolism genes was altered during postnatal heart development, suggesting an unexplored role of this essential metabolism pathway in regulating regeneration capacity loss during development. Our further studies found that SphK2, a key kinase in the sphingomyelin metabolism pathway, as well as its metabolite S1P, dramatically upregulated during heart repair. Moreover, SphK2 knockout mice completely lost the ability to regenerate their heart after birth, whereas AAV9-mediated SphK2 overexpression efficiently restored cardiac damage after myocardial infarction in the adult mice. In addition, RNA-seq analyses revealed that genes of the E2F family might contribute to the SphK2/S1P-regulated heart regeneration..We will detailedly profile the dynamic changes of S1P and other sphingomyelin metabolite during heart development and regeneration, and in the same time, illustrate the molecular mechanism that underlined the SphK2/S1P-induced CM proliferation and heart regeneration by multiple cutting-edge techniques. In summary, this study will deepen our understanding of the mechanism behind heart regeneration, and provides theoretical basis for the establishment of new myocardial infarction treatment strategies through targeting the key metabolism pathways.