G-protein receptor signalling in CNS endothelial cells and its role in supporting lymphocyte migration

白细胞(白细胞)从血液进入身体的固体组织是免疫系统的正常功能。这一过程涉及一系列事件，从白细胞黏附到血管壁开始，然后穿透并迁移到组织之外。这一现象得到了广泛的研究，并描绘了这一过程的主要步骤。然而，这一事件的分子基础仍然知之甚少。直到最近，人们还认为迁移在很大程度上是由白细胞决定的，血管壁的内皮细胞为白细胞的附着提供了点。越来越多的证据表明，内皮细胞在调节白细胞迁移中发挥着积极的作用，这一观点现在受到了挑战。在大脑和视网膜中可能尤其如此，因为血管形成了比其他组织更难渗透的屏障。来自多个实验室的最新数据表明，内皮细胞表面黏附受体的激活导致一系列生物信号的诱导，从而导致积极支持白细胞通过血管屏障的迁移。一些内皮信号已经被描述，特别是由结合循环白细胞的细胞黏附分子ICAM-1介导的信号。然而，很明显，其他信号通路必须在内皮细胞内运行，以调节白细胞在不同组织血管系统和炎症反应的不同阶段的差异迁移。我们最近报道，激活内皮细胞上的G蛋白偶联受体(GPCR)是白细胞成功通过脑血管屏障迁移所必需的。因此，这个项目的目的是为了更好地了解由于激活这种GPCR而发生的基本生物学事件，并阐明它在控制白细胞迁移中的作用。该项目所产生的信息将有助于更好地理解支持白细胞迁移到大脑和视网膜的细胞生物学。这一点尤其重要，因为不需要的白细胞进入这些器官在多发性硬化症和视网膜炎症等疾病中发挥着重要作用。增加我们对负责这一进程的基本机制的了解，将使我们能够确定生物事件序列中的关键目标，以便进行治疗干预，从而改进此类疾病的治疗战略。

The traffic of white blood cells (leukocytes) from the blood into the solid tissues of the body is a normal function of the immune system. This process involves a sequence of events starting with leukocyte adhesion to the blood vessel wall followed by penetration and migration into the tissue beyond. This phenomenon has been studied extensively and the main steps in the process delineated. However, the molecular basis of this event remains poorly understood. Until recently, it was believed that migration was largely determined by the leukocyte, with the endothelial cells of the blood vessel wall providing points for leukocyte attachment. This view has now been challenged by emerging evidence that the endothelial cell plays a pro-active role of in regulating leukocyte migration. This may be especially true in the brain and retina where the blood vessels form a more impermeable barrier than in other organs.Recent data from various laboratories shows that activation of surface adhesion receptors on the endothelial cell leads to the induction of a sequence of biological signals that result in active support of leukocyte migration through the vascular barrier. Some of the endothelial signalling has been characterised, especially that mediated by the cell adhesion molecule ICAM-1 which binds circulating leukocytes. It is clear, however, that other signalling pathways must operate within the endothelial cells to regulate differential leukocyte migration across the vasculature of different tissues and at different stages of the inflaqmmatory response. We have recently reported that activation of a G-protein coupled receptor (GPCR) on the endothelial cell is necessary for successful leukocyte migration through the vascular barriers of the brain. The aim of this project, therefore, is to gain a greater understanding of the fundamental biological events that occur as a result of activation of this GPCR and to elucidate its role in controlling leukocyte migration. Information resulting from this project will lead to a greater understanding of the cell biology underpinning leukocyte migration into the brain and retina. This is especially important as unwanted leukocyte traffic into these organs play a major role in diseases such as multiple sclerosis and retinal inflammation. Increasing our knowledge of the basic mechanisms responsible for this process will allow us to identify key targets in the biological sequence of events that would be accessible to therapeutic intervention and hence lead to improved treatment strategies for such diseases.