TMEM16A和ClC-3 Cl-通道参与脑血管重构的内在相互关联的分子机制及药物干预的研究

在前国家自然科学基金重点项目的资助下,已发现Cl-通道是一有效阻遏脑血管重构的新靶点。TMEM16A Ca2+激活与ClC-3容积调节Cl-通道均使[Cl-]i下降，但参与脑血管重构的方式刚好相反, 提示在高血压脑血管重构中，TMEM16A与ClC-3 Cl-通道相互间有内在关联。本项目拟在ClC-3敲除及TMEM16A敲除DOCA-盐高血压小鼠，SHRSP及双肾双夹易卒中高血压大鼠上，采用斑片钳离子通道记录, 荧光影象测定胞浆Cl- 及分子生物学等技术,进一步探讨TMEM16A与ClC-3 Cl-通道在脑血管重构中的内在关联机制；寻找ClC-3 Cl-通道降低[Cl-]i激活的Cl-敏感蛋白激酶，其信号通路，及与脑血管重构的关系;他汀类药物干预后的影响；为进一步揭示Cl-通道在脑血管重构作用的分子基础，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。

Under the NNSFC foundation support, we have found that Chloride channel is a new target for the blocking cerebrovascular remodeling. Although both of TMEM 16A Ca2+ activated and ClC-3 volume regulated Cl- channels evoked a decrease in the cytoplasma Cl- level ([Cl-]i), these channels mediated the cerebrovascular remodeling in reverse manner, suggesting that there is an interaction between TMEM 16A Ca2+ activated and ClC-3 volume regulated Cl- channels in the development of cerebrovascular remodeling. In this study, we would like to use spontaneously hypertensive rat two kidney two clip hypertensive rat, DoCa- salt hypertensive TMEM16A knockout and ClC-3 knockout mice for the investigating the interaction of two channels in the development of cerebrovascular remodeling, underling mechanisms and the kinas of sensitivity to the [Cl-]i change by ClC-3 channel, with patch clamp single channel recording, image and biomolecular techniques. Also we would like to determine the influence of statin-treatment. This study will provides a very important data to identify that chloride channel is a new target for the development the new drug for the treatment of cerebrovascular remodeling and stroke, and to further explain the molecular mechanism of chloride channels effect on cerebrovascular remodeling.