MALAT1/miR-204/Smad4信号通路介导间质细胞成骨分化诱导主动脉瓣钙化机制研究

项目名称： MALAT1/miR-204/Smad4信号通路介导间质细胞成骨分化诱导主动脉瓣钙化机制研究

项目编号： No.81500300

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： 王勇军

作者单位： 华中科技大学

项目金额： 18万元

中文摘要： 主动脉瓣钙化发病率逐年增高，严重危害人类健康。我们前期工作发现：miR-204作用下调与主动脉瓣钙化密切相关，可作为研究主动脉瓣钙化发病机制的重要靶点，但具体调控机制仍有待进一步阐明。最新研究表明：长链非编码RNA（lncRNA）能以竞争性内源RNA的形式抑制miRNA。生物信息学软件分析显示lncRNA MALAT1具有miR-204的结合位点，miR-204能靶向抑制Smad4。我们初步发现：在诱导钙化的瓣膜间质细胞中MALAT1表达显著升高，过表达MALAT1可进一步下调miR-204表达，miR-204受到抑制后，Smad4蛋白表达可上调。本课题拟在此基础上，检测MALAT1、miR-204及Smad4 在主动脉瓣钙化中的表达相关性；在细胞和动物水平，观测MALAT1/miR-204/Smad4信号通路在介导间质细胞成骨分化诱导主动脉瓣钙化中的作用，为主动脉瓣钙化的防治提供新靶点。

中文关键词： 主动脉瓣钙化；长链非编码RNA；miR-204；Smad4

英文摘要： Aortic valve calcification (AVC) is a common clinical problem with increased morbidity and mortality and afflicts our aging population. However, the mechanism of AVC has not been thoroughly understood. Our previous study showed that the down-regulation of miR-204 is closely associated with the progression of AVC, and could be used as a target for exploring novel treatment strategies. The precise molecular mechanism involved in the effects of miR-204 on AVC has still to be fully discovered. Recently, lncRNAs have been reported to act as an effective miRNA sponge and affect miRNA target gene activity. Bioinformatic analysis shows that the lncRNA MALAT1 have a miR-204 binding site, and that miR-204 can specifically bind to the 3’-untranslated region (3’-UTR) of Smad4. We also found that MALAT1 was markedly downregulated in BMP-2-stimulated aortic valve interstitial cells (VICs), and that over-expression of MALAT1 in VICs resulted in decreased miR-204 level and thereby increased the protein expression of Smad4. Base on these findings, this study will systematically evaluate the expressions of MALAT1, miR-204 and Smad4 in AVC, investigate the influence of MALAT1/miR-204/miR-204 signal pathway on the osteoblast differentiation of VICs, and thus provide novel approaches for the treatment of AVC.

英文关键词： aortic valve calcification;lncRNA;miR-204;Smad4