p53转录后多样化修饰在糖尿病心肌纤维化的发生及进展中的机制研究

项目名称： p53转录后多样化修饰在糖尿病心肌纤维化的发生及进展中的机制研究

项目编号： No.81500219

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： 刘军辉

作者单位： 西安交通大学

项目金额： 18万元

中文摘要： 糖尿病心肌病（DCM）是糖尿病重要并发症，长期慢性高糖可刺激心肌成纤维细胞分泌I型和III型胶原，加速心肌纤维化和心脏重构。课题组前期发现：1）使用AMPK激动剂白藜芦醇可抑制I型胶原合成，降低心肌纤维化改善DCM；2）p53是I型胶原一个新的核转录因子，且高糖诱导p53及乙酰化p53在成纤维细胞聚积。p53受多种磷酸化及乙酰化修饰调节，在心血管的作用尚未阐明。我们推测高糖通过抑制AMPK活性，抑制p53的Ser15、Ser392位点磷酸化，加速DNA损伤；高糖还可抑制SIRT1表达，使得乙酰化p53积聚，引起I型胶原转录、表达及分泌增加，促进心肌纤维化和DCM的发生发展。本课题拟采用离体、在体及基因敲除小鼠等多种技术阐明p53多样化修饰对心肌成纤维细胞DNA损伤及I型胶原表达的调节作用及机制，明确AMPK/SIRT1对p53的多样化修饰和调控的作用机制，为探索DCM调节治疗靶点提供依据。

中文关键词： 心肌纤维化；磷酸腺苷激活的蛋白激酶；p53；白藜芦醇；；I型胶原

英文摘要： Diabetic cardiomyopathy(DCM) is an important complication of diabetes. It is well established that chronic high blood suger stimulates cardiac fibroblast to secret collagen I and III, speeding up the process of cardic fibrosis and remodelling. Our recent research data found that AMPK activator resveratrol could inhibit the production of collagen I, reducing the degree of cardiac fibrosis and improving DCM in mice. In addition, Lucifarase experiment indicated that p53 might be a new nuclear transcription factor for collagen I. Furthermore, in the presence of high sugar, p53 and ac-p53 tends to accumulate in fibroblast. p53 is a well known tumour suppressor gene. Phosphoryation and aceytlation are important processes involved in the function of p53, whose roles are not fully understood in the regulation of cardiovascular system. Herein, We speculate that 1) high blood sugar inhibit phosphorilation of p53 at Ser15 and Ser392, which enhance DNA damage through inactivation of AMPK; and 2) high sugar inhibits the expression of SIRT1, making Ac-p53 accumulation，which causes the transcription, expression and secreation of Collagen I, which induces cardiac fibrosis, and promotes the initiation and progression of DCM. We propose to elucidate the The role of multiple post-transcriptional modification of p53 on DNA damage and Collagen I expression in cardiac fibroblast using in vitro, in vivo and knockout mice models. We also propose to establish the mechnisms of AMPK/SIRT1 in p53 modification and regulation, which could potencially facilitate novel therapeutic targets in DCM.

英文关键词： Cardiac fibrosis;AMPK;p53;Resveratrol;Collagen I