TGR5受体在高糖刺激下心肌细胞功能调控中的作用及信号转导机制

项目名称： TGR5受体在高糖刺激下心肌细胞功能调控中的作用及信号转导机制

项目编号： No.31300946

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： 冯健

作者单位： 泸州医学院

项目金额： 21万元

中文摘要： 糖代谢异常引起氧化应激，导致心肌功能受损。TGR5受体是近来发现的代谢调节开关，激动TGR5受体有利于改善机体糖代谢，减轻氧化应激。申请者前期研究发现TGR5受体激动剂能导致血管平滑肌细胞Nrf2核转位，激活HO-1的表达，减轻氧化损伤。但目前尚不知TGR5受体在高糖刺激下心肌细胞功能调控中的作用及受体后信号转导机制。现有的研究表明激动TGR5能引起心肌细胞Akt和GSK-3b磷酸化。因Akt和GSK-3b是激活Nrf2的上游因子，故推测Nrf2/HO-1途径可能参与了TGR5调控高糖环境下心肌细胞功能。因此，本项目拟采用心肌细胞，结合分子生物学及形态学技术，以信号蛋白磷酸化、细胞内钙瞬变、细胞凋亡及肥大等为主要观察指标，阐明激动TGR5受体对高糖时心肌细胞功能的影响及分子机制。这些问题的解决有望从基因转录调控角度再认识TGR5受体的作用及其机制，丰富心血管受体学理论。

中文关键词： TGR5；信号通路；心肌细胞；高糖；

英文摘要： Oxidative stress induced by abnormal glucose metabolism contributes to impaired cardiac function. The G protein-coupled receptor TGR5 has recently been recognized as a novel metabolic switch. TGR5 activation can improve the metabolism of glucose and reduce oxidative stress. Our previous study has shown that the TGR5 receptor agonist can increase Nrf2 nuclear translocation and subsequent upregulation of HO-1, which reduce oxidative stress injury. However, the role of TGR5 in modulation of cardiomyocytes function under high glucose and related signal transduction mechanism remain unclear. The current study shows that TGR5 activation can cause phosphorylation of Akt and GSK-3b in cardiomyocytes. Akt and GSK-3b are upstream regulators of Nrf2 activation. Thus, we hypothesized that Nrf2/HO-1 are involved in TGR5-mediated regulation of cardiomyocytes function in which Akt and GSK-3b are likely to participate. Using cardiomyocytes, the present study has been performed to investigate the protective effect of TGR5 activation against high glucose-induced dysfunction on cardiomyocytes and whether Nrf2/HO-1 signaling pathway is involved. In the study, Phosphorylation of signaling proteins, intracellular calcium transients, cell apoptosis and hypertrophy will be measured by molecular biology and morphological techniques. The

英文关键词： TGR5；signaling pathway；cardiomyocyte；glucose；