干预TRPC5 通道对动脉粥样硬化易损斑块的稳定作用及其机制研究

项目名称： 干预TRPC5 通道对动脉粥样硬化易损斑块的稳定作用及其机制研究

项目编号： No.81470558

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 马志勇

作者单位： 山东大学

项目金额： 73万元

中文摘要： 易损斑块破裂是急性冠状动脉综合征（ACS）的始动环节，斑块内炎症是引起易损斑块的关键因素。近年经典型瞬时感受器电位（TRPC）通道在巨噬细胞炎症反应中的作用受到重视，我们前期发现TRPC5通道与斑块不稳定性相关，为了探讨干预TRPC5通道能否稳定易损斑块及其机制，本研究以apoE(-/-)鼠为基础、颈总动脉套管加限制性应激的方法建立破裂率更高的与人类易损斑块相似的动物模型，体内利用siRNA技术降低TRPC5通道表达，进行超声影像学、病理学和分子生物学实验研究其能否稳定易损斑块，降低斑块炎症反应。体外培养巨噬细胞，通过基因沉默TRPC5通道后，综合利用膜片钳、细胞内钙离子成像、分子和细胞生物学技术探讨TRPC5通道在巨噬细胞炎症反应中的作用及其信号转导通路，以明确其稳定易损斑块的机制。由于离子通道是细胞膜表面蛋白，更易进行药物干预，这些结果对于防治ACS必将产生重要的理论价值和社会价值。

中文关键词： 易损斑块；炎症反应；钙库操纵型钙通道；巨噬细胞

英文摘要： Acute coronary syndrome (ACS) is the major cause of mortality and morbidity, in which vulnerable atherosclerotic plaque rupture is the most common and initial causes of ACS. Local inflammation plays a key role in unstability of atherosclerotic plaque. Rencently, canonical transient receptor potential channels (TRPC) show important effect on regulating inflammatory reaction of macrophages. Our study found that TRPC5 channel was positively related with plaque instability. To explore the role of TRPC in plaque unstability and the mechanism, we establish an animal model of plaque unstability in apoE-/- mice under a high-fat diet by a combination of perivascular carotid collar placement and restrictive stress. We knockdown TRPC5 channel using siRNA technique and investigate effects of TRPC5 channel on plaque unstability using micro-ultrasound measurement, histological and molecular biological experiments. In addition, transfecting macrophages with siRNA of TRPC5, we study the mechanism of TRPC5 in regulating inflammatory reaction and its signal transduction pathways. Meanwhile, TRPC5 is membrane proteins that have generally provided good sites for drug action, so the results provide with theoretical basis and social value for prevention and treatment of acute cardiovascular and cerebrovascular events.

英文关键词： Vulnerable plaque;Inflammation;Store operated calcium channel;Macrophage