金属蛋白酶ADAMTS13表达调控的机制研究

项目名称： 金属蛋白酶ADAMTS13表达调控的机制研究

项目编号： No.81470487

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： 周洲

作者单位： 中国医学科学院阜外医院

项目金额： 80万元

中文摘要： 冠状动脉心脏病（冠心病）是威胁人类生命健康的重要疾病。血栓形成造成冠状动脉的堵塞是导致心肌梗死的直接原因。研究表明，金属蛋白酶ADAMTS13可以通过剪切VWF蛋白调节血栓形成，其功能降低与冠心病密切相关。ADAMTS13主要合成于肝星状细胞和血管内皮细胞，但调节机制尚不清楚。本课题组利用小鼠肝纤维化模型，证明肝组织中miR882和miR185升高,而ADAMTS13 mRNA与蛋白含量相应降低。因可在细胞间传递生物学物质，外泌小体正成为研究热点。本课题组发现外周血的外泌小体中，ADAMTS13 mRNA及相关miRNA的变化与肝组织中一致，提示外泌小体中的生物学信息可反映肝脏的功能状态。本申请将阐明与miRNA对ADAMTS13转录的调控机制，揭示肝星状细胞间及其与血管内皮细胞间外泌小体介导的信号传递，并研究外泌小体进行机体内物质转运来调节ADAMTS13的表达以及心肌保护的可行性。

中文关键词： 金属蛋白酶ADAMTS13；微小RNA；外泌小体；冠心病

英文摘要： Coronary artery disease (CAD) is the major threat to the healthy life. The thrombi formed inside the vessels block the coronary arteries, which leads to myocardial infarction. Previous studies have shown that the metalloprotease ADAMTS13 specifically cleaves VWF to regulate the thrombus formation. The reduction of ADAMTS13 has been associated with the initiation and progress of CAD. Hepatic stellate cells and endothelial cells are the major source for ADAMTS13 in plasma, but the regulation of ADAMTS13 expression is still unknown. According to database, miR882 and miR185, which are predicted to bind the 3'UTR of ADAMTS13, might be two major miRNAs regulating ADAMTS13 transcription. In line with the prediction, we observed increased miR882 and miR185 levels in hepatic stellate cells of mice with liver cirrhosis, while ADAMTS13 expression in the livers was decreased. Exosomes, small vesicles containing nucleic acid and protein, are important in intercellular communication. Our preliminary data has also shown that the changes of ADAMTS13 mRNA, miR882 and miR885 in exosomes isolated from circulation were consistent with that in cirrhotic livers, indicating that the information carried by exosomes reveals the liver conditions. In the present study, we will further determine the regulatory mechanism of miRNAs on ADAMTS13 transcription. Furthermore, we will elucidate the intercellular communication by exosomes between hepatic stellate cells, as well as hepatic stellate cells and vascular endothelial cells. Lastly, we will investigate whether the infusion of exosomes containing miRNAs and ADAMTS13 protein will alter ADAMTS13 expression and play a role in myocardial ischemia/reperfusion injury in mice.

英文关键词： ADAMTS-13;microRNA;exosome;coronary artery disease