心肌高表达mi-99a改善心肌梗死后心室重构及其机制研究

项目名称： 心肌高表达mi-99a改善心肌梗死后心室重构及其机制研究

项目编号： No.81200092

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 顾蓉

作者单位： 南京大学

项目金额： 23万元

中文摘要： 心肌梗死是危及人民健康的致死性疾病之一,减少病理性心室重构是心肌梗死后治疗的关键。MEK1-ERK1/2、mTOR在心肌缺氧、肥大刺激时均激活。MEK1-ERK1/2激活利于心肌细胞增厚（thickness），抑制心肌细胞延长，减少左心室扩大，改善心功能；mTOR激活增加心肌梗死后病理性肥厚、心肌炎症，减少自噬，促进心功能恶化。最近在肿瘤细胞中的研究发现MEK1-ERK1/2通过下调mir-99a表达间接引起mTOR蛋白表达增加，提示MEK1-ERK1/2、mTOR之间相互作用，相互平衡。申请者计划在小鼠心肌梗死模型中通过心肌内直接注射高表达mir-99a的质粒，抑制mTOR而不减少MEK1/2的表达，使心肌梗死后心肌向有利于减少病理性重构方向发展。研究结果将为临床改善心肌梗死预后提供新的理论与方法。

中文关键词： microRNA；缺血性心脏病；细胞凋亡；自噬；基因治疗

英文摘要： Myocardial infarction is a primary cause of morbidity and mortality in the worldwide. Attenuates the cardiac pathologic remodeling has become the predominant strategies after myocardial infarction. Previous studies has shown that both the MEK1-ERK1/2 and mTOR signaling pathway are activated in response to myocardial hypoxia and hypertrophic stimuli. The activation of MEK1-ERK1/2, increase myocyte thickness, decrease myocyte lengthening, reduce left ventricular dilatation, and improve cardiac function. While, the activation of mTOR, increases cardiac pathological hypertrophy and inflammation, decreases autophagy ,worsen cardiac function. One recent study reveals that MEK1-ERK1/2 can down-regulating mir-99a expression indirectly to increased the expression of mTOR in tumor cells, suggesting that MEK1-ERK1/2 and mTOR interact with each other and reach a blance. To observe and explore the role of mir-99a during the ventricular remodeling, we plan to inject mir-99a plasmid into the myocardium in a mouse model of myocardial infarction, and to suppress the mTOR without the damage of MEK1/2, which contribute to attenuates the cardiac pathologic remodeling after Myocardial infarction. This study will provide the new evidence for theoretical basis and practical applications to improve the prognosis of myocardial infarcti

英文关键词： microRNA；ischemic heart disease；apoptosis；autophagy；gene therapy