心衰是威胁人类健康的重大疾病，目前治疗不能从根本上解决心衰心肌大量缺失的问题，已知哺乳动物心肌在出生后极短时间内具有较强的再生能力，研究心肌再生的关键机制和促进心肌再生的有效方法有望突破心衰治疗中的瓶颈难题。我们新近发现心肌条件性敲除1-磷酸鞘氨醇受体1型（S1PR1）导致新生小鼠心肌再生受损，基因表达芯片示凋亡相关基因上调和增殖相关基因下调，实验表明S1PR1激活PI3K/AKT和ERK通路，已知这些通路调控细胞凋亡、细胞增殖、心肌纤维化和心肌成熟，据此提出假说：心肌细胞S1PR1在PI3K/AKT和ERK介导下调控心肌细胞凋亡、细胞增殖、心肌纤维化和心肌成熟，从而影响心肌再生。本课题采用条件性基因敲除小鼠和基于Cas9的基因敲减技术，在心肌再生模型上，结合体外机制研究，阐明S1PR1在心肌再生中的作用和机制，尝试通过细胞靶向性激活S1PR1信号以促进心肌再生，为临床治疗心衰提供新方法。

Heart failure is a serious and expensive public health problem worldwide; however, modern therapy hardly solves the problem caused by loss of cardiomyocytes in heart failure patient. It has been well documented that mammalian hearts had the capability to regenerate cardiomyocyte and completely recover after heart injury within a limited time window after birth. Understanding molecular mechanisms of heart regeneration and exploring new strategies to boost heart regeneration holds great promises for curing heart failure. .Sphingosine 1-phosphate receptor 1 (S1PR1) plays an important role in the regulation of cardiovascular functions. It has been shown that S1PR1 was expressed in cardiomyocytes (CMs). Our preliminary investigations showed cardiac specific loss of S1PR1 retarded the process of heart regeneration in neonatal mice. Our further gene expression microarray revealed that multiple apoptosis-related genes were up-regulated and proliferation-related genes were down-regulated in the hearts of CM specific S1PR1-deletion mice, indicating that CM-expressing S1PR1 controls CM apoptosis and survival. Meanwhile, our histological investigation showed that specific S1PR1-deletion mice displayed more apoptotic cardiomyocytes (CMs), less proliferating CMs, more severe cardiac fibrosis and disorganized sacromere, compared to wild-type control mice. Our further in vitro experiments showed that S1P/S1PR1 activated PI3K/AKT and ERK pathway, which has been well documented as essential pathways to regulate cell apoptosis and survival, cell proliferation, cardiac fibrosis and cardiomyocyte maturation. We therefore hypothesize that CM-expressing S1PR1 regulates heart regeneration via PI3K/AKT and ERK pathway by influencing CM apoptosis, proliferation, cardiac fibrosis and CM maturation. We will use multiple tissue conditional knock-out mice and Cas9-based gene knock-down mice, and establish heart regeneration model in these mice to investigate the role of S1PR1 for heart regeneration. Meanwhile, we will undertake microarray-based high-throughout gene expression profiling method and in vitro experiments to investigate the detailed mechanism by which S1PR1 controls cardiomyocyte proliferation, survival and apoptosis, cardiac fibrosis and cardiomyocyte maturation. Furthermore, we will establish cell-target gene expressing delivery system on the basis of gene-modified AAV and apply this system to deliver S1PR1 gene or its downstream key molecules to probe whether this strategy can activate and enhance heart regeneration after myocardial infarction. Taken together, this project will uncover a novel role of S1PR1 in heart regeneration and its underlying molecular mechanism. Most importantly, our project will raise a new and promising therapeutic option for heart failure treatment.