SUMO化修饰FXR受体调控糖尿病心肌损伤的机制研究

项目名称： SUMO化修饰FXR受体调控糖尿病心肌损伤的机制研究

项目编号： No.81500221

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 袁安彩

作者单位： 上海交通大学

项目金额： 18万元

中文摘要： 氧化应激及炎症触发心肌细胞凋亡和纤维化是糖尿病致心肌损伤的重要病理生理机制，是导致DCM患者心力衰竭和死亡的主要原因。配体激活FXR抑制TNF-α和IL-1β等炎症因子转录表达可以显著减少活性氧(氮)自由基生成，减轻DCM心肌纤维化及心肌细胞凋亡。然而调控这些炎症因子表达的分子机制目前尚不清楚。SUMO化修饰在调控转录因子反式阻遏基因表达中发挥重要作用。结合前期研究基础，我们推测SUMO化修饰FXR抑制炎症因子表达是其发挥抗心肌损伤作用的关键机制。为证实以上假说，本课题拟通过体外高糖培养心肌细胞和在SUMO基因敲除DCM小鼠模型中，采用RNAi、Co-IP及ChIP等技术明确SUMO化修饰调控 FXR反式阻遏TNF-α和IL-1β等炎症因子表达，从而抑制氧化应激、细胞凋亡与重构的作用并探讨其可能机制，为阐明糖尿病心肌损伤机制提供新线索。

中文关键词： 糖尿病心肌病；氧化应激；SUMO化修饰；核受体FXR；炎症细胞因子

英文摘要： Oxidative stress triggered cardiomyocyte apoptosis and fibrosis is an important pathophysiological mechanism of diabetic cardiomyopathy (DCM). And it is the main cause of heart failure and death in patients with DCM. Inhibitory effect of FXR on the expression of TNF-α and IL-1β can significantly reduce reactive oxygen/nitrogen species generated and inhibit DCM myocardial oxidative stress. However, the regulation mechanism of these inflammatory factors is still not clear. SUMOylation of transcription factor plays an important role in the trans-repressor genes expression regulation. Combined with the basis of preliminary studies, we speculate that the SUMOylation of FXR inhibiting of inflammatory factors is a key mechanism of their anti-inflammation activity. To confirm this hypothesis, we will use RNAi, Co-IP and ChIP to investigate SUMOylation regulate FXR, which in turn trans-repress the expression of TNF-α and IL-1β, inhibit oxidative stress, attenuate apoptosis and remodeling in high glucose-treated cardiomyocyte in vitro and in vivo SUMO-KO DCM mice model. Exploring this possible mechanism, we can provide new clues to clarify the role of FXR in DCM.

英文关键词： Diabetic Cardiomyopathy;Oxidative Stress;SUMOylation;Nuclear Receptor FXR;Inflammatory Factor