BRG1上调动脉平滑肌细胞PIEZO1表达在TAD形成中的作用机制研究

Mounting evidence supports the notion that thoracic aortic dissection (TAD) is the result of biomechanical weakening of the aortic media. Previous studies showed that aortic smooth muscle cells (SMCs) phenotypic transition from the contractile to the synthetic type might result in instability of the aortic media, which are responsible for the occurrence of TAD..In a recent work we demonstrated that the expression of BRG1 is up-regulated in the aortic SMCs of TAD, and that its overexpression can induce aortic SMC phenotypic transition from the contractile to the synthetic type. These data suggest that up-regulation of BRG1 expression in aortic SMCs contribute to the development of TAD. In addition, we found that BRG1 significantly upregulate the expression of PIEZO1, which reportedly as a mechanically activated ion channel. These data suggest that BRG1 might regulate SMC phenotype transition through the PIEZO1-mediated pathway. However, the mechanisms that underlie BRG1-mediated regulation of PIEZO1 expression and SMC phenotype transition warrant further investigation..In this project, we propose to evaluate the role of BRG1/PIEZO1 in the SMCs phenotypic transition by multiple approaches including bioinformatic analysis, luciferase reporter assay, RNA interference, ChIP, Chip, and clinical investigation. Conceivably, elucidation of the molecular pathways involved in the regulation of the SMCs phenotypic transition in TAD by BRG1 will provide important clues for the development and evaluation of novel therapies against TAD.

动脉平滑肌细胞(SMC）由收缩型向合成型转化导致的管壁薄弱是胸主动脉夹层(TAD)发生发展的重要病理基础。我们在前期首次发现，染色质改构复合物SWI/SNF的核心亚基BRG1在TAD组织中的表达水平显著高于正常组织；过表达BRG1可诱导动脉SMC由收缩型向合成型转化；此外我们还发现具有令细胞感受压力刺激的重要基因PIEZO1的启动子区含有SWI/SNF潜在识别位点。据此我们推测：BRG1可通过上调PIEZO1表达促动脉SMC向合成型转化。本项目拟通过ChIP、荧光素酶报告基因实验明确BRG1对PIEZO1转录的促进作用，并通过表达谱芯片结合细胞功能实验探讨BRG1通过上调PIEZO1表达促动脉SMC向合成型转化的分子机制。另外，我们还将通过临床统计分析明确BRG1/PIEZO1途径中关键基因表达与体内动脉SMC表型转化及TAD发病的相关性，为进一步探索TAD发病机制提供依据。