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

CNS 内皮细胞中的 G 蛋白受体信号传导及其在支持淋巴细胞迁移中的作用

• 批准号: G0501451/1
• 负责人: John Greenwood
• 金额: $ 58.61万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0501451%2F1
• 关键词: protein; receptor; signalling; CNS; endothelial

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.

白血球（白细胞）从血液中进入身体的实体组织是免疫系统的正常功能。这个过程包括一系列的事件，从白细胞粘附到血管壁开始，然后渗透和迁移到血管壁以外的组织。人们对这一现象进行了广泛的研究，并描述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提供附着点。这一观点现在被新的证据所挑战，即内皮细胞在调节白细胞迁移中起着积极的作用。在大脑和视网膜中尤其如此，那里的血管形成了比其他器官更不易渗透的屏障。来自不同实验室的最新数据表明，内皮细胞表面粘附受体的激活可诱导一系列生物信号，从而积极支持白细胞通过血管屏障迁移。一些内皮信号已经被表征，特别是由细胞粘附分子ICAM-1介导的，ICAM-1结合循环白细胞。然而，很明显，内皮细胞内必须有其他信号通路来调节白细胞在不同组织和炎症反应的不同阶段在脉管系统中的差异迁移。我们最近报道了内皮细胞上g蛋白偶联受体（GPCR）的激活是白细胞成功通过脑血管屏障迁移的必要条件。因此，该项目的目的是为了更好地了解由于该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使我们更好地理解细胞生物学的基础，即白细胞迁移到大脑和视网膜。这一点尤其重要，因为进入这些器官的多余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事件序列中的关键目标，这些目标将可用于治疗干预，从而导致改进此类疾病的治疗策略。