CircRNA Igf1r通过吸附miR-15家族联合调控CHK1/AKT/YAP表达启动心肌梗死后心肌再生的作用机制研究

心肌梗死后心肌再生治疗是目前研究的热点。我们2020年发表在《Circulation》的研究显示CHK1激酶可促进心梗后心肌再生，但相关上游机制尚未阐明。我们从靶向调控CHK1的miR-15家族入手，筛选获得在新生心脏短暂高表达的circ-Igf1r。预实验示过表达circ-Igf1r可恢复CHK1表达，且促心肌增殖效果强于CHK1；进一步研究发现过表达circ-Igf1r可同时上调AKT和YAP表达。因此推测circ-Igf1r通过靶向抑制miR-15家族，促进CHK1/AKT/YAP表达而启动心肌再生程序。本项目中我们将明确circ-Igf1r对心肌细胞增殖的作用；运用转基因小鼠验证其对心梗后心肌再生和心功能的影响；阐明circ-Igf1r通过miR-15家族联合调控CHK1/AKT/YAP表达发挥作用的相关分子网络机制。本项目将为心梗后心肌再生治疗奠定理论基础并提供新的强效治疗靶点。

The treatment of cardiac regeneration after myocardial infarction (MI) is the focus of current research. Our study published in Circulation in 2020 indicated that myocardial overexpression of CHK1 could improve cardiac regeneration post MI, but the relevant upstream mechanism has not been clarified. Started with the miR-15 family members that target CHK1, we screened and obtained circ-Igf1r whose high expression in neonatal hearts was transient. Preliminary experiments showed that overexpression of circ-Igf1r could restore the expression of CHK1, and the effect of it on promoting cardiac proliferation was stronger than CHK1. We further found that overexpression of circ-Igf1r could up-regulate both AKT and YAP expression, therefore it was speculated that circ-Igf1r could initiate cardiac regeneration procedure by targeting inhibition of the miR-15 family and then promoting the expression of CHK1/AKT/YAP. In this project, we will clarify the role circ-Igf1r plays in the proliferation of cardiomyocytes, demonstrate the effect of circ-Igf1r on myocardial regeneration and cardiac function post MI by utilizing transgenic mice, and finally elucidate the relevant molecular mechanisms in which circ-Igf1r functions by jointly regulating the expression of CHK1/AKT/YAP through miR-15 family. The project will lay a theoretical foundation for the treatment of cardiac regeneration and provide a new potent therapeutic target after MI.