炎症反应是造成缺血性卒中后血脑屏障（blood-brain barrier，BBB）结构和功能破坏的重要原因，引起炎症反应的关键因素是白细胞与血管内皮细胞的粘附、外渗。TMEM16A蛋白是新发现的钙离子激活Cl-通道的分子基础，在真核生物组织广泛表达，与炎症反应有关。我们前期研究发现，小鼠脑血管内皮细胞中表达TMEM16A，一侧大脑中动脉栓塞小鼠模型梗死侧皮层的TMEM16A表达增高，而TMEM16A抑制剂可显著减少缺血性卒中小鼠的梗死体积、减少血脑屏障破坏；体外炎症模型中抑制TMEM16A蛋白可减少内皮细胞分泌粘附分子。本项目，我们将采用TMEM16A基因敲除鼠制备体内外缺血小鼠模型，利用分子生物学、病理学等技术研究靶向抑制TMEM16A蛋白，探讨TMEM16A在缺血性脑卒中后对血脑屏障的病理作用，以及可能的分子机制，为缺血性卒中临床治疗提供新思路和尝试。

Inflammatory reaction plays a pivotal role in the blood-brain barrier (BBB) destruction following ischemic brain injury. Enhanced leukocyte adhesion to vascular endothelial cell is an essential event in inflammatory process. TMEM16A, a newly discovered protein regulating the calcium-activated chloride channels (CaCCs), is widely expressed in eukaryotes. Recently, some researches have suggested that TMEM16A is associated with inflammation. What’s more, our preliminary results demonstrated that TMEM16A was expressed in vascular endothelial cells of mouse brain and TMEM16A was up-regulated after middle cerebral artery occlusion (MCAO) in mice. With the application of TMEM16A inhibitor, infarct volume was significantly decreased and the permeability of BBB was also rescued in MCAO models. Likewise, in cultured endothelial cells, TMEM16A inhibitor profoundly downregulated the expression levels of adhesion molecules after the LPS and TNF-α stimulation. Therefore, in this project, using TMEM16A conditional knock-out mice and biological techniques, we aim to further confirm that targeted inhibition of TMEM16A exerts protective effects on BBB integrity following ischemic brain injury and to explore the potential molecular mechanisms. In conclusion, this research may provide a novel clinical treatment combating BBB destruction in ischemic stroke.