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

YAP信号通路在脑卒中血脑屏障功能障碍和重塑机制中的作用

• 批准号: 2779254
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2779254
• 关键词: role; YAP; signalling; pathway; mechanisms

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.

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，这对于维持血脑屏障（BBB）完整性和大脑功能至关重要。但是，中风后，BBB经历了与紧密连接的分解，ECM重塑和ECM蛋白质酶降解相关的深刻变化。细胞因子白介素（IL）-1是与BBB功能障碍和随后的组织损伤相关的促炎反应的已建立介质。尽管已知IL-1在中风的急性阶段发挥有害作用，但越来越多的证据表明，IL-1的双相作用在中风后的亚急性阶段表现出神经释放性能。此外，CNS损伤后的ECM重塑与BBB修复有关，并且已显示IL-1介导修复机制，导致假设由IL-1驱动的BBB修复可以通过ECM重塑来调节。实际上，我们最近已经证明了laminin-10（LM-10）是缺氧损伤和IL-1B诱导的体外炎症后参与BBB修复的关键ECM分子。 YAP/HIPPO途径最近引起了极大的兴趣，因为它与ECM重塑有关的极具动态途径，并且可以很好地确定ECM-整合素信号传导是启动YAP途径的关键步骤。至关重要的是，我们最近证明，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。但是，这些发现与中风结果和恢复以及中风中YAP信号通路的潜在靶向的体内相关是完全未知的。因此，该项目的目的是进一步研究ECM重塑过程中YAP信号通路的作用，并在体外进行炎症对BBB功能障碍和修复，并测试靶向ECM / YAP信号途径轴的体内相关性，可以在Stroke后利用功能恢复。