circRNA-CRGL调控心肌细胞增殖介导心梗后心肌再生的分子机制研究

Myocardial infarction is a life-threatening condition for people health in China. Due to the loss of the proliferation ability of adult cardiomyocytes, myocardial regeneration after myocardial infarction is limited. Recent studies have shown that circRNAs are involved in the development of tumor, Alzheimer disease and other diseases, but the role and mechanism of circRNAs in cardiomyocyte proliferation and myocardial regeneration is still unclear. In our preliminary study, we found that circRNA-CRGL can inhibit the proliferation of cardiac myocytes, and the silencing of circRNA-CRGL can promote myocardial regeneration and improve cardiac function after myocardial infarction, which indicates circRNA-CRGL is a critical regulator of cardiac regeneration. The present project will employ molecular cloning, RNA pull down, Luciferase and other methods to study: (1) whether circRNA-CRGL plays a role in the regulation of myocardial cell proliferation and myocardial regeneration; (2) revealed the underlying mechanism of circRNA-CRGL regulating cardiac regeneration; (3) if targeting circRNA-CRGL can promote cardiac regeneration and improve heart functions after myocardial infarction. This study will provide the new target and strategy for the treatment of myocardial infarction in the future.

心肌梗死严重危害我国人口健康，成人心梗后心肌细胞因失去增殖能力而无法再生，如何重新激活心肌细胞增殖潜能已成为诱导心肌再生的关键。新近研究发现circRNAs与肿瘤、痴呆等疾病发生密切相关，但是circRNAs是否参与调控心肌细胞增殖和心梗后心肌再生尚不清楚。在前期研究中我们发现一个circRNA-CRGL可显著抑制心肌细胞增殖，相反敲减circRNA-CRGL可使心肌细胞重新获得增殖潜能，提示其是调控心肌再生的新靶点。本项目拟联合运用分子克隆、RNA pull down、Luciferase等实验技术研究：（1）circRNA-CRGL是否可通过调控心肌细胞增殖介导心梗后心肌再生；（2）阐明circRNA-CRGL调控心肌细胞增殖和心肌再生的分子信号通路；（3）以circRNA-CRGL为调控靶点是否可通过促进心肌再生提高梗死心脏功能。本研究将为临床上心肌梗死的再生治疗提供新靶点和新策略。

靶向心肌细胞可塑性已成为促进心肌梗死后心脏修复的新策略。然而，调控心脏再生的分子机制网络尚不完全清楚。作为非编码RNA，环状RNA（circRNAs）在调节心脏生理学和病理学方面发挥着重要作用。本研究旨在探讨circMdc1在损伤后心脏修复中的调控作用，并阐明其潜在机制。我们发现circMdc1的表达水平在出生后小鼠心脏中上调，但在再生修复的心肌中下调。进一步发现circMdc1是氧化应激敏感型circRNA，过表达circMdc1抑制心肌细胞增殖，而沉默circMdc1导致心肌细胞的细胞周期重新进入。在体内实验中，心脏特异性腺相关病毒介导的circMdc1敲减促进了心脏再生修复，同时改善了心脏功能。相反，circMdc1过表达减弱了心尖切除后新生心脏的再生能力。此外，circMdc1能够通过与PABP结合来阻断其宿主基因Mdc1的翻译，从而影响DNA损伤和心肌细胞的染色体稳定性。综上，氧化应激敏感的circMdc1通过调节心肌细胞的DNA损伤和染色体稳定性影响心肌细胞增殖潜能，进而在损伤后的心脏再生和心脏修复中发挥重要作用。