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: 6720934
• 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/6720934
• 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）：越来越多的证据体现出炎症是伴随脑缺血发作的神经元组织死亡和破坏神经元组织的重要原因。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细胞因子，粘合分子和主要趋化因子和主要趋化因子的多样性提供的分子信号的策划相互作用将高度破坏性的白细胞引导到大脑中。特别是，趋化因子单核细胞化学吸引蛋白1（MCP-1）被认为是驱动脑部浸润后脑实质的主要效应子之一。此外，在血液脑屏障（BBB）的血管周间空间中，MCP-1的分泌和存在​​不仅意味着它们在趋化梯度的组成中的作用，而且在可能激活内皮细胞和接口复合物的重排中。为了阐明MCP-1在炎症反应过程中的新型功能，我们提出了一个针对以下假设进行测试的研究计划：MCP-1引起脑内皮细胞连接复合物的重排，因此有助于在炎症反应和炎症反应和疗程 - 疗程 - 再生效果（I/R）受伤（I/R）中的BBB渗透性改变。具体而言，我们将研究MCP-1对体外脑内皮渗透性的影响（脑内皮细胞的纯化培养以及星形胶质细胞和内皮细胞的CO培养）和体内（将MCP-1注射到脑部实质或脑部实质性或脑脑室内）。此外，我们将估计MCP-1对使用体外和体内缺血再灌注损伤模型在炎症反应过程中对BBB渗透性的实际影响。总的来说，这些研究的结果将为开发新的治疗策略提供基础，以减少中枢神经系统中中风的破坏以及其他炎症过程。