我们已有工作发现脑血管平滑肌细胞TMEM16A氯通道表达和活性变化与高血压诱导的脑血管重构呈负相关，TMEM16A平滑肌特异性过表达可抑制脑血管重构的发展，但其机制尚不清楚。预实验结果显示TMEM16A过表达可抑制基底动脉平滑肌细胞迁移，降低AngII诱导的integrin表达和肌球蛋白轻链MLC20的磷酸化; 并可抑制G蛋白的胞浆胞膜转位。本项目拟在这些研究基础上，将TMEM16A平滑肌特异性敲除和高表达的AngII高血压小鼠整体实验与基因沉默、过表达和定点突变等离体实验结合起来，从分子和离子通道水平研究TMEM16A氯通道在脑血管重构中的作用与其调控平滑肌细胞迁移的关联性，其机制与信号通路；及影响TMEM16A的药物干预后的变化。为进一步阐明平滑肌细胞迁移在脑血管重构过程中的作用和机制，并为防治高血压脑血管重构及脑卒中等并发症的新药研发提供新靶点奠下基础。

We have found that the expression and activity of TMEM16A chloride channel are decreased in cerebrovascular smooth muscle cells during hypertension, and negatively correlated with basilar artery remodeling. Smooth muscle-specific TMEM16A overexpression inhibited the development of hypertension-induced cerebrovascular remodeling. However, the underling mechanisms are still unknown. Our pilot experiments showed that overexpression of TMEM16A by adenovirus transfection inhibited AngII induced basilar artery smooth muscle cell migration. TMEM16A decreased AngII induced integrin expression and MLC20 phospharylation, as well as the translocation of G protein from cytosol to plasma membrane. In this study, we would like to use TMEM16A smooth muscle-specific knockout and overexpression hypertensive mice, together with the adenovirus transfection and gene mutation techniques, to investigate the relationship between TMEM16A regulated cerebrovascular remodeling and smooth muscle cell migration, the underling mechanisms, and the influence of drug treatment trargeting on TMEM16A. This study will provide very important data to identify that TMEM16A chloride channel is a new target for the development of new drug for the treatment of cerebrovascular remodeling and stroke, and to further explain the molecular mechanism of chloride channels effect on cerebrovascular remodeling.