Chemokine Effects on Blood-brain Barrier Permeability

趋化因子对血脑屏障通透性的影响

• 批准号: 6823224
• 负责人: ANUSKA V. ANDJELKOVIC-ZOCHOWSKA
• 金额: $ 24.73万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6823224
• 关键词: angiography; astrocytes; biological signal transduction; blood brain barrier; cerebral hemorrhage; cerebral ischemia /hypoxia; chemoattractants; chemokine; enzyme linked immunosorbent assay; immunofluorescence technique; inflammation; laboratory mouse; leukocytes; mannitol; membrane permeability; mixed tissue /cell culture; monocyte chemoattractant protein 1; polymerase chain reaction; reperfusion; tight junctions; western blottings

DESCRIPTION (provided by applicant): The increasing body of evidence implicates inflammation as a significant contributor to death and destruction of neuronal tissue that accompanies an episode of a cerebral ischemia. During the acute inflammatory response to ischemia/reperfusion (I/R) condition, highly destructive leukocytes are directed into the brain by an orchestrated interplay of molecular signals provided by diversity of cytokines, adhesive molecules and mainly chemokines. In particular, the chemokine monocyte chemoattractant protein-1 (MCP-1) is considered to be one of the main effectors driving postischemic infiltration into the brain parenchyma. Furthermore, secretion and existence of MCP-1 in the perivascular space of blood brain barrier (BBB) implicates their role not only in the composition of chemoattract gradient but also in the possible activation of endothelial cells and rearrangement of the junction complexes. In order to elucidate a novel possible function of MCP-1 during an inflammatory response, we propose a research plan directed at testing of the following hypothesis: MCP-1 induces rearrangement of brain endothelial cells junction complexes and thus contributes to alteration in the BBB permeability during inflammatory response and ischemial-reperfusion (I/R) injury. Specifically we will investigate effect of MCP-1 on brain endothelial permeability in vitro (purified culture of brain endothelial cells as well as co culture of astrocytes and endothelial cells) and in vivo (injection of MCP-1 into the brain parenchyma or intracerebroventricular). Also, we will estimate real effect of MCP-1 on BBB permeability during an inflammatory reaction using in vitro and in vivo model of ischemia reperfusion injure. Collectively, results from these studies will provide a foundation for developing novel therapeutic strategies to lessen the ravages of stroke as well as other inflammatory process in CNS.

描述（由申请人提供）：越来越多的证据表明炎症是脑缺血发作时神经元组织死亡和破坏的一个重要因素。在对缺血/再灌注（I/R）条件的急性炎症反应期间，高度破坏性的白细胞通过由多种细胞因子、粘附分子和主要趋化因子提供的分子信号的精心策划的相互作用被引导到大脑中。特别是，趋化因子单核细胞趋化蛋白-1 (MCP-1) 被认为是驱动缺血后浸润脑实质的主要效应器之一。此外，MCP-1在血脑屏障（BBB）血管周围空间的分泌和存在​​表明它们不仅在趋化梯度的组成中发挥作用，而且在内皮细胞的可能激活和连接复合物的重排中发挥作用。为了阐明 MCP-1 在炎症反应过程中可能的新功能，我们提出了一项研究计划，旨在检验以下假设：MCP-1 诱导脑内皮细胞连接复合物重排，从而有助于改变 BBB 通透性炎症反应和缺血再灌注（I/R）损伤期间。具体来说，我们将在体外（脑内皮细胞的纯化培养物以及星形胶质细胞和内皮细胞的共培养）和体内（将MCP-1注射到脑实质或脑室内）研究MCP-1对脑内皮通透性的影响。此外，我们将使用缺血再灌注损伤的体外和体内模型来估计 MCP-1 在炎症反应期间对 BBB 通透性的实际影响。总的来说，这些研究的结果将为开发新的治疗策略奠定基础，以减轻中风以及中枢神经系统其他炎症过程的破坏。