心房纤颤诱导心肌纤维化发生新机制-分泌型microRNA-328

项目名称： 心房纤颤诱导心肌纤维化发生新机制-分泌型microRNA-328

项目编号： No.31300943

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 梁海海

作者单位： 哈尔滨医科大学

项目金额： 25万元

中文摘要： 心房纤颤（房颤）是最常见的恶性心律失常之一，房颤患者常常伴有心肌纤维化，最终导致心力衰竭。然而，房颤诱导心肌纤维化的分子机制尚未被揭示。microRNAs在多种心脏疾病中发挥重要作用，近来研究发现microRNAs在生物体内稳定存在，且可以在细胞间传递。本课题将证明microRNA-328通过旁分泌形式从心肌细胞转运至成纤维细胞，介导房颤诱导的心肌纤维化；同时利用转基因动物及细胞共培养技术探索microRNA-328的分泌机制及形式；并进一步证明microRNA-328通过靶向作用于成纤维细胞TGFβRⅢ，激活TGF-β1信号通路，进而促进成纤维细胞分泌大量胶原，引起心肌纤维化；最终通过在体及离体实验证实特异性敲减microRNA-328具有减轻心肌纤维化的作用。本项目的研究不仅可以拓展我们对房颤诱导的心肌纤维化这一重大科学问题的认识，而且将为房颤引起的心肌纤维化及心衰的防治提供理论基础。

中文关键词： 心肌纤维化；旁分泌；微小核糖核酸；长链非编码RNA；TGF-β1信号通路

英文摘要： Atrial fibrillation (AF) is one of the most common malignant arrhythmias. Patients with AF often accompany with myocardial fibrosis and eventually have heart failure. However, the mechanism of AF-induced myocardial fibrosis has not been well understood. microRNAs play important roles in a variety of cardiac diseases. Recent studies have found that microRNAs are stable in vivo, and can be transported between cells. This study aims to prove that microRNA-328 can be secreted from cardiomyocytes to cardiac fibroblasts and mediate AF-induced myocardial fibrosis. Transgenic animals and cell co-culture will be used to explore the secretion mechanism of microRNA-328. And, we further verify that microRNA-328 could activate the TGF-β1 pathway by inhibiting TGFβRⅢ and then contribute to the increase of collagen content in fibroblasts to cause myocardial fibrosis. Finally, we confirm that knock down of microRNA-328 could alleviate myocardial fibrosis in vivo and in vitro. This project can not only expand the understanding of the mechanism of atrial fibrillation induction of myocardial fibrosis, but also provide a theoretical basis for the prevention and treatment of myocardial fibrosis and heart failure due to atrial fibrillation.

英文关键词： Cardiac Fibrosis；paracrine；microRNAs；long non-coding RNAs；TGF-β1 pathway