心脏施旺细胞分泌蛋白Reln对心肌细胞增殖和心脏再生作用的研究

成年哺乳动物心肌细胞增殖能力微弱，心脏受损后难以再生。如何增强心肌细胞的增殖能力是再生生物学的重点和难题。最近研究发现心脏神经系统可促进心肌细胞增殖，但其机制还未被阐明。申请人发现分泌蛋白质Reln可以促进心肌细胞增殖，其在心脏中由施旺细胞特异性表达，而心肌细胞分泌蛋白质Thbs1则抑制心肌细胞增殖。有趣的是，心肌细胞高表达的Vldlr是Reln和Thbs1的共同受体。因此我们推测心脏施旺细胞通过分泌Reln拮抗Thbs1对心肌增殖的抑制。本项目将检验Reln、Thbs1以及Vldlr突变小鼠的心肌梗死后再生的表型，以及检验外源Reln对小鼠心脏再生的影响，阐明Reln/Vldlr信号通路对心肌细胞增殖的作用；并在心肌细胞中解析其下游信号通路，阐明施旺细胞调节心肌细胞增殖的分子机制。本项目针对心脏神经系统调控心脏再生新机制的研究将为治疗心肌梗死提供新的药物靶点和治疗手段。

Mammalian heart cannot regeneration after ischemic injury because mature cardiomyocytes cannot proliferate. Thus it is crucial for cardiac regenerative medicine to find ways to promote cardiomyocyte proliferation. Recent studies discovered that the neural system in the heart can promote cardiomyocyte proliferation, while the underlying mechanism is still largely unknown. In our preliminary studies, we found that Reln secreted by schwann cells in the heart, can promote cardiomyocyte proliferation in vitro, and Thbs1 which is secreted by cardiomyocytes inhibits cardiomyocyte proliferation. Interestingly, both Reln and Thbs1 functions through the same receptor, Vldlr. Therefore, we hypothesize that schwann cells in the heart secrets Reln to counteract the inhibitory effect of the abundant Thbs1 on cardiomyocyte proliferation. To test our hypothesis, we propose to study the effect of Reln/Thbs1/Vldlr signaling pathway on cardiomyocyte proliferation, by examining the cardiac regeneration after myocardial infarction of mice carrying null mutations of Reln, Thbs1 and Vldlr, as well as mice treated with exogenous Reln; and to study the intracellular signaling pathway downstream of Reln/Thbs1/Vldlr in the cardiomyocytes, which will offer new theories of schwann cells regulating cardiomyocyte proliferation. Our proposed research on dissecting mechanisms through which cardiac neural cells regulating cardiomyocyte proliferation and cardiac regeneration will provide new drug tas) and possible therapeutic method(s) to treat myocardial infarction.