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）为神经血管单元的细胞提供了一个结构和功能环境，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、ECM的重塑和ECM蛋白的酶降解有关。细胞因子白细胞介素(IL)-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介质。虽然已知IL-1在中风急性期发挥有害作用，但越来越多的证据表明，IL-1的双相作用在中风后亚急性期表现出神经修复特性。此外，中枢神经系统损伤后的ECM重塑与血脑屏障修复有关，而IL-1已被证明介导修复机制，从而提出IL-1驱动的血脑屏障修复可能受ECM重塑调节的假设。事实上，我们最近在体外证明了层粘连蛋白-10 （laminin-10, LM-10）是参与缺氧损伤和il - 1b诱导炎症后血脑屏障修复的关键ECM分子。最近，YAP/Hippo通路作为一种涉及ECM重塑的极其动态的通路获得了极大的兴趣，并且已经确定ECM整合素信号传导是启动YAP通路的关键步骤。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靶基因和血管生成标志的差异表达。然而，这些发现与卒中预后和恢复的体内相关性以及YAP信号通路在卒中中的潜在靶向性是完全未知的。因此，本项目的目的是进一步研究体外ECM重塑和炎症过程中YAP信号通路对血脑屏障功能障碍和修复的作用，并测试靶向ECM / YAP信号通路轴在脑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.