BBB损坏是临床上脑卒中最严重的后果之一。目前已知卒中后BBB损坏的重要机制是MMP-2/9的激活。我们近期的研究表明，脑内皮细胞(EC)的结构变化(actin异常聚合及连接蛋白重分布)是缺血再灌损伤造成早期BBB通透性增高的一个新的机制。HSP27在许多CNS疾病模型中具有保护作用，除了广为人知的蛋白伴侣和抗凋亡功能外，HSP27也许存在额外的作用，如重塑肌动蛋白丝以及抑制炎症反应。我们近期研究发现，HSP27在I/R损伤后的EC中有短暂上调。然而，HSP27对I/R损伤后EC功能的维持及其潜在机制还不清楚。因此，本课题利用EC-过表达HSP27转基因鼠，拟验证在I/R损伤早期HSP27通过稳定微血管内皮细胞的细胞骨架和抑制MMP2/9以及促炎蛋白产生，从而保护BBB完整性。此外，将利用纳米-HSP27药物治疗年轻和老年鼠I/R损伤，为纳米-HSP27药物的临床前研究提供理论基础。

BBB damage is one of the most disabling consequences of stroke in the clinic. While matrix metalloproteinase (MMP) 2/9 activation, a predominant mechanism thought to contribute to post-stroke BBB disruption. Our recent studies suggested that structural alterations in brain endothelial cells (EC), including abnormal actin polymerization and the resulting redistribution of junctional proteins. In addition to its well-known protein chaperone and anti-apoptotic functions, HSP27 may act as a potent actin depolymerization factor in certain cell types such as EC, thus potentially inhibiting actin polymerization-mediated BBB disruption. We recently observed that HSP27 is transiently upregulated in brain EC after I/R. However, the precise role of HSP27 in the functional integrity of EC following I/R and the underlying mechanism remain unknown. This proposal will further explore the BBB protective effect of HSP27 on I/R brain injury and elucidate the underlying mechanisms. The central hypothesis to be tested is that HSP27 protects BBB against I/R injury by stabilizing EC cytoskeletal organization in microvasculature early after I/R and inhibiting the production of MMP2/9 as well as pro-inflammatory proteins by using we have created conditional Tg mice overexpressing HSP27 specifically in EC. Furthermore, we will test the post-stroke delivery of nano-HSP27 particles to EC protects against BBB damage and improves outcomes in both young adult and aged mice. These novel findings support the therapeutic potential of nano-HSP27 against I/R brain injury for preclinical studies.