TRAF1在心肌梗死后心室重构中的作用及分子机制

The ventricular remodeling after myocardial infarction is one of the main pathological basis to cause heart failure, but therapeutic option is limited at present. The role of native immunity in myocardial repair after myocardial infarction and ventricular remodeling attracts more and more attention. TRAF1 is a kind of adaptor protein, which is important both in native immunity and acquired immunity, but its function in ventricular remodeling after myocardial infarction and the mechanism is not clear. In this study, we hope to discover the role of TRAF1 in inflammatory response , apoptosis, cardiomyocyte hypertrophy and myocardial fibrosis after myocardial infarction. At animal level, acute myocardial infarction (AMI) models are established by using TRAF1 gene knock mice and cardiac-specific TRAF1 transgenic mice, to study the sufficiency and necessity of TRAF1 in ventricular remodeling after myocardial infarction and its molecular mechanism. At cellular level, the primary cardiomyocytes of TRAF1 gene knock and transgenic mice are isolated and cultured, and to study the function of TRAF1 in the inflammation and apoptosis procedure of cardiomyocytes. At the molecular level, the mechanism of TRAF1, which relates to the ventricular remodeling after myocardial infarction is studied by using the molecular biology techniques. It is hoped to provide a theoretical basis for the prevention and new therapeutic targets of heart failure after myocardial infarction.

心肌梗死后的心室重构是导致心衰的主要病理基础之一，但迄今尚无确切的治疗手段。天然免疫在心梗后心肌修复及心室重构中的作用正日益受到重视。TRAF1是一种衔接蛋白，在天然免疫和获得性免疫中均发挥重要作用，但其对心肌梗死后心室重构的作用及其机理尚未见报道。本研究从动物、细胞、分子三个水平探讨TRAF1对心梗后炎症反应、细胞凋亡、心肌细胞肥大及心肌纤维化的作用。动物水平，应用TRAF1基因敲除小鼠和心脏特异性TRAF1转基因小鼠建立急性心梗模型，研究TRAF1对心梗后心室重构的影响及分子机理；细胞水平，分离培养TRAF1敲除及转基因小鼠原代心肌细胞，在低氧及正常环境下模拟心肌缺血再灌注损伤,并应用分子生物学技术，在分子水平系统阐明TRAF1影响心梗后心室重构的作用机制，为预防心梗后心力衰竭和研究新的治疗靶点提供理论依据。

心肌梗死后的心室重构是导致慢性心力衰竭的主要病理基础之一，以左心室进行性扩张及心功能恶化为特征，迄今尚无明确的治疗方法。肿瘤坏死因子受体相关因子1(TRAF1)是一种细胞内接头蛋白。现有研究表明，TRAF1在天然免疫和获得性免疫中有重要作用，并且参与细胞凋亡的调控。然而，TRAF1在心肌梗死中的作用尚无报道。本项目研究发现，在缺血性心肌病患者及小鼠梗死后的左室心肌组织中，TRAF1蛋白表达水平显著升高。在小鼠心肌梗死动物模型中，本研究发现TRAF1基因敲除可以显著改善心梗后小鼠生存率及左室重构，而TRAF1过表达则显著加重了心梗后的不良事件。利用体外培养的新生小鼠原代心肌细胞，本研究从动物，细胞及分子水平阐明：TRAF1通过促进心梗后心肌组织炎症反应及心肌细胞凋亡，加重心肌梗死后的心室重构。本项目研究阐明了TRAF1在心肌梗死后心室重构过程中的作用及发挥作用的分子机制，为心肌梗死后的心室重构的治疗及预防提供了新策略。