Chemokine Effects on Blood-brain Barrier Permeability

描述(由申请人提供)：越来越多的证据表明，炎症是伴随脑缺血发作而导致的死亡和神经元组织破坏的重要因素。在对缺血/再灌注(I/R)状态的急性炎症反应中，高度破坏性的白细胞通过多种细胞因子、黏附分子和主要是趋化因子提供的分子信号的协调相互作用而被引导到脑内。特别是，趋化因子单核细胞趋化蛋白-1(MCP-1)被认为是推动缺血后脑实质渗透的主要效应因子之一。此外，血脑屏障(BBB)血管周围间隙中MCP-1的分泌和存在不仅参与趋化梯度的组成，而且可能参与内皮细胞的激活和连接复合体的重排。为了阐明MCP-1在炎症反应中可能的新功能，我们提出了一项研究计划，旨在验证以下假设：MCP-1诱导脑内皮细胞连接复合体重排，从而有助于炎症反应和缺血再灌注损伤过程中血脑屏障通透性的改变。具体地说，我们将在体外(脑内皮细胞的纯化培养以及星形胶质细胞和内皮细胞的共培养)和体内(脑实质或脑室内注射MCP-1)研究MCP-1对脑内皮细胞通透性的影响。此外，我们将使用体外和体内的缺血再灌注损伤模型来评估MCP-1在炎症反应中对血脑屏障通透性的真实影响。总而言之，这些研究的结果将为开发新的治疗策略提供基础，以减轻中风的破坏以及中枢神经系统的其他炎症过程。

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.