The role of the YAP signalling pathway in mechanisms of blood-brain barrier dysfunction and remodelling after stroke

中枢神经系统(CNS)的细胞外基质(ECM)为神经血管单位的细胞提供结构和功能环境，对维持血脑屏障(BBB)的完整性和脑功能至关重要。然而，中风后，血脑屏障发生了深刻的变化，与紧密连接的破坏，细胞外基质的重塑和细胞外基质蛋白的酶降解有关。细胞因子白介素1是与血脑屏障功能障碍和随后的组织损伤相关的促炎反应的公认介质。虽然已知IL-1在卒中急性期发挥有害作用，但越来越多的证据表明，在卒中后的亚急性期，IL-1具有双相作用，表现出神经修复特性。此外，中枢神经系统损伤后的ECM重塑与BBB修复有关，而IL-1被证明介导了修复机制，这导致了假设由IL-1驱动的BBB修复可能受ECM重塑的调节。事实上，我们最近证明了层粘连蛋白-10(LM-10)是一种关键的ECM分子，参与了体外缺氧损伤和IL-1B诱导的炎症后的BBB修复。YAP/Hippo通路作为一种与细胞外基质重塑有关的极其动态的通路，最近引起了人们的极大兴趣，而ECM-整合素信号通路是YAP通路启动的关键步骤。重要的是，我们最近证明了IL-1B和LM-10调节内皮细胞中的YAP信号通路，导致YAP靶基因的差异表达和血管生成的标志。然而，这些发现与卒中结局和康复的体内相关性以及YAP信号通路在卒中中的潜在靶点是完全未知的。因此，本项目的目的是在体外进一步研究YAP信号通路在ECM重塑和炎症对BBB功能障碍和修复中的作用，并测试靶向ECM/YAP信号通路轴在卒中后功能恢复中的体内相关性。

The extracellular matrix (ECM) of the central nervous system (CNS) provides a structural and functional environment for the cells of the neurovascular unit that is essential for maintenance of blood-brain barrier (BBB) integrity and brain functions. However, after stroke, the BBB undergoes profound changes associated with the breakdown of tight junctions, remodelling of the ECM and enzymatic degradation of ECM proteins. The cytokine interleukin(IL)-1 is an established mediator of the pro-inflammatory response associated with BBB dysfunction and subsequent tissue damage. Although IL-1 is known to exert detrimental actions during the acute phase of stroke, increasing evidence suggests a biphasic action of IL-1 that exhibits neuroreparative properties during the sub-acute phase after stroke. Furthermore, ECM remodelling after CNS injury is associated with BBB repair, and IL-1 has been shown to mediate repair mechanisms, leading to the hypothesis that BBB repair driven by IL-1 could be regulated by ECM remodelling. Indeed, we have recently demonstrated laminin-10 (LM-10) as a key ECM molecule involved in BBB repair after hypoxic injury and IL-1B-induced inflammation in vitro. The YAP/Hippo pathway has recently gained significant interest as an extremely dynamic pathway implicated in ECM remodelling, and it is well established that ECM-integrin signalling is a key step in the initiation of the YAP pathway. Critically, we have recently demonstrated that IL-1B and LM-10 regulated YAP signalling pathway in endothelial cells leading to differential expression of YAP target genes and hallmarks of angiogenesis. However the in vivo relevant of those findings on stroke outcome and recovery and the potential targeting of the YAP signalling pathway in stroke is completely unknown. The aim of this project is therefore to further investigate the role of the YAP signalling pathway during ECM remodelling and inflammation on BBB dysfunction and repair in vitro, and to test the in vivo relevance that targeting the ECM / YAP signalling pathway axis can be exploited for functional recovery after stroke.