miR-130a靶向Gax调控Rap1A表达在胸主动脉瘤血管平滑肌细胞表型转化中的作用及机制研究

项目名称： miR-130a靶向Gax调控Rap1A表达在胸主动脉瘤血管平滑肌细胞表型转化中的作用及机制研究

项目编号： No.81500366

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： 郑辉

作者单位： 上海交通大学

项目金额： 17万元

中文摘要： 血管平滑肌细胞（VSMCs）表型转化所导致的主动脉中层薄弱是胸主动脉瘤发生的重要病理基础。研究揭示生长终止特异性同源盒（Gax）转录因子在VSMCs表型转化中起重要作用。我们研究显示：Gax在升主动脉瘤中表达降低；在预测靶向Gax基因的miRNAs中发现miR-130a的可能性大，其在升主动脉瘤和骨桥蛋白诱导VSMCs表型转化中表达上调；在Gax过表达的VSMCs中发现Rap1A表达变化最显著，Rap1A对收缩型VSMCs标志物表达、VSMCs增殖和迁移有影响。但miR-130a靶向Gax调控Rap1A表达在胸主动脉瘤VSMCs表型转化中的具体作用仍有待于明确。本项目拟在此基础上通过采用ChIP、细胞实验及临床标本等方法从基因、细胞和组织水平上确定胸主动脉瘤VSMCs表型转化中存在miR-130a-Gax-Rap1A调控轴，将为阐明胸主动脉瘤发病机制提供新思路，为防治胸主动脉瘤提供新靶标。

中文关键词： 胸主动脉瘤；血管平滑肌细胞；表型转化；微小RNA

英文摘要： Vascular smooth muscle cells phenotypic modulation leading to aortic tunica media weakening is the important pathologic basis of the formation and development of thoracic aortic aneurysm. Previous studies have showed that growth arrest-specific homeobox (Gax) transcription factor plays a key role in the process of VSMCs phenotypic modulation. Our prophase researches showed that the expression of Gax in human ascending aortic aneurysm wall was significantly decreased. In previous trials, we found miR-130a was a good possibility in the prediction of miRNAs targeted to the 3’-untranslated region (3’-UTR) of Gax gene, and miR-130a expression was significantly increased in human ascending aortic aneurysm specimens and the process of VSMCs phenotypic switching induced by osteopontin (OPN). Our studies also showed the most significant change of Rap1A expression was found in VSMCs over-expressing Gax, and Rap1A had an effect on the expression of markers for VSMCs contractile phenotype, and VSMCs proliferation and migration. However, the specific roles of miR-130a targeting Gax-regulated Rap1A expression in VSMCs phenotypic modulation in thoracic aortic aneurysm are still needed to be confirmed. On this basis we will carry on macro and micro researches at the gene, cell and tissue level using the methods of ChIP, cells experiment, clinical specimens and so on to clarify that miR-130a-Gax-Rap1A axis exists in VSMCs phenotypic modulation in thoracic aortic aneurysm, which will help give further new insight into the pathogenesis of thoracic aortic aneurysm and provide new possible target molecules for prevention and treatment for thoracic aortic aneurysm.

英文关键词： Thoracic aortic aneurysm;Vascular smooth muscle cells;Phenotypic modulation;MicroRNA