骨髓间充质干细胞旁分泌BDNF调控TRPC6通道抗心肌缺血作用及其机制

项目名称： 骨髓间充质干细胞旁分泌BDNF调控TRPC6通道抗心肌缺血作用及其机制

项目编号： No.81200077

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： 赵静

作者单位： 哈尔滨医科大学

项目金额： 23万元

中文摘要： 骨髓间充质干细胞（BMSCs）通过旁分泌作用治疗缺血性心肌病成为近年来研究热点，但其确切调节机制有待进一步深入探讨。我们前期研究发现心肌细胞中TRPC6通道蛋白在心肌缺血时表达发生异常，提示其可能参与心肌缺血病理生理过程，并且有研究表明脑缺血时神经细胞中TRPC6通道与BMSCs及其旁分泌的脑源性神经营养因子（BDNF）密切相关。因此本项目提出如下科学假设：BMSCs通过旁分泌BDNF与TrkB受体结合，激活PLC-DAG通路调控心肌细胞膜上TRPC6通道，TRPC6通道激活后上调ERK、CAMKⅡ、CREB表达，抑制心肌细胞凋亡，修复缺血受损心肌。本项目拟从动物、细胞及分子水平应用分子生物学、电生理学及基因转染等技术深入探讨BMSCs旁分泌BDNF调控TRPC6通道修复缺血心肌的作用机制，为寻找新的抗心肌缺血药物靶点提供理论基础，同时为临床干细胞移植治疗缺血性心肌病提供新依据。

中文关键词： 心肌缺血；脑源性神经营养因子；瞬时受体电位通道；细胞凋亡；

英文摘要： The therapeutical role of bone marrow mesenchymal stem cells (BMSCs) by its paracrine effect for ischemic heart disease (IHD) has been paid more and more attention nowadays. However, the underlying regulatory mechanisms remain deeply discussed. Our previous studies found that the protein expression of TRPC6 channel in cardiomyocytes was dysregulated in myocardial ischemia (MI), which implied that TPRC6 channel may participate in the pathophysiological process of MI. Furthermore, studies also indicated that TRPC6 channel was closely related to BMSCs and the paracrined brain derived neurotrophic factor(BDNF) in ischemic neurons. Thus, the present project hypothesized that: BMSCs paracrines BDNF which combines with TrkB receptor, then activates PLC-DAG signaling pathway and regulates TRPC6 channel in the membrane of cardiomyocytes. TRPC6 channel further activates downstream signaling pathways. The protein expression of ERK, CAMKⅡand CREB is upregulated to suppress the apoptosis of cardiomyocytes to repair the injured myocardium. Molecular biological, electrophysiological and gene transfection methods were employed in our project to explore the potential mechanisms of TRPC6 channel in cardiac repair of BMSCs for ischemic myocardium, which providing the rational for novel anti-myocardial ischemic drug targets and ste

英文关键词： myocardial ischemia；BDNF；TRPC；apoptosis；