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

白色血细胞（白细胞）从血液进入身体的实体组织是免疫系统的正常功能。该过程涉及一系列事件，开始于白细胞粘附到血管壁，随后渗透并迁移到组织中。这一现象已被广泛研究，并描绘了该过程的主要步骤。然而，这一事件的分子基础仍然知之甚少。直到最近，人们认为迁移主要是由白细胞决定的，血管壁的内皮细胞为白细胞附着提供了点。这一观点现在受到了新出现的证据的挑战，即内皮细胞在调节白细胞迁移中起着积极的作用。这在脑和视网膜中可能尤其如此，在脑和视网膜中，血管形成比其他器官中更不渗透的屏障。最近来自各个实验室的数据表明，内皮细胞上的表面粘附受体的激活导致诱导一系列生物信号，这些信号导致主动支持白细胞迁移通过血管屏障。一些内皮信号转导的特征，特别是介导的细胞粘附分子ICAM-1结合循环白细胞。然而，很明显，其他信号通路必须在内皮细胞内起作用，以调节不同组织的血管系统中和炎症反应的不同阶段的不同白细胞迁移。我们最近报道了内皮细胞上G蛋白偶联受体（GPCR）的激活对于白细胞成功迁移通过脑血管屏障是必要的。因此，本项目的目的是更好地了解由于GPCR激活而发生的基本生物学事件，并阐明其在控制白细胞迁移中的作用。从这个项目中得到的信息将导致对支持白细胞迁移到大脑和视网膜的细胞生物学的更深入的理解。这一点尤其重要，因为进入这些器官的不必要的白细胞在多发性硬化症和视网膜炎症等疾病中起着重要作用。增加我们对这一过程的基本机制的了解，将使我们能够确定生物学事件序列中的关键目标，这些目标将可用于治疗干预，从而改善此类疾病的治疗策略。

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.