CNS Inflammation in Nervous and Mental Disease

超出提供的空间。趋化因子单核细胞趋化蛋白(MCP-1)和巨噬细胞炎性蛋白-1α(MLP-1α)在炎症发作期间经常在大脑中观察到，因此被认为是引导白细胞向中枢神经系统(CNS)渗透的关键因素。然而，没有直接证据表明这两种趋化因子中的任何一种实际上都能刺激白细胞通过高度不通透的血脑屏障(BBB)迁移。此外，目前还完全不清楚这些趋化因子是如何产生的。它们主要来源于血管周围胶质细胞和渗出的白细胞，在血脑屏障中发挥作用。鉴于这些物质可能对神经炎症性疾病的病程和治疗产生深远影响，解决这些问题至关重要。为此，建议通过实验来检验以下假设：趋化因子MCP-1和MIP1-a刺激单核细胞跨血脑屏障迁移，并通过与脑微血管内皮细胞的特定相互作用实现这一点。具体地说，实验旨在澄清以下问题：1)MCP-1或mipl-cc单独具有刺激跨血脑屏障跨内皮细胞迁移的能力吗？或者每个都需要与其他促炎细胞因子协同工作？2)这些趋化因子通过什么机制(S)可能通过血脑屏障传递它们的信号？最初的实验将使用人类血脑屏障的体外模型。为直接检测MCP-1和MLP-1a对单核细胞跨内皮细胞迁移的影响。接下来的一系列研究将利用这一模型和分离的人脑微血管来研究这些趋化因子是通过细胞旁还是跨细胞转运通过专门的脑微血管内皮细胞。后续的研究将确定这些趋化因子的识别受体是否存在于血管闭塞的微血管表面，如果存在，则检查它们在趋化因子运输中的作用。最后的实验将阐明微血管对趋化因子刺激的反应，例如，黏附分子表达和通透性的改变，这可能支持白细胞的渗透。这项研究将首次描述MCP-1和MLP-1a在血脑屏障的相互作用。此外，认识到MCP-1和MLP-1a在中枢神经系统炎症中的重要作用，这些实验将极大地帮助理解这种疾病的发病机制，并开发新的治疗方法来拮抗神经炎症性疾病中的趋化因子作用。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. The chemokines monocyte chemoattractant protein (MCP-1) and macrophage inflammatory protein-1 alpha (MlP-la) are regularly observed in the brain during episodes of inflammation, and thus, are thought to be critical effectors in directing leukocyte infiltration into the central nervous system (CNS). Nevertheless, no direct evidence exists that either one of these two chemokines can actually stimulate leukocyte migration through the highly-impermeable blood-brain barrier (BBB). Moreover, it is completely unclear how these chemokines. which derive mainly from perivascular glia and extravasated leukocytes, exert their actions across the BBB. In light of the profound impact these substances could have on the course and treatment of neuroinflammatory disease, it is crucial that these issues be resolved. Toward this end, experiments are proposed to test the following hypothesis: Chemokines MCP-1 and MIP1- a stimulate mononuclear migration across the BBB, and do so by specific interactions with brain microvascular endothelial cells. Specifically, experiments will be aimed at clarifying the following issues: 1) Does MCP-1 or MIPl-cc, alone, have the capacity to stimulate transendothelial migration across the BBB. or does each need to work in concert with other proinflammatory cytokines? 2) By what mechanisms(s) might these chemokinesrelay their signals across the BBB? Initial experiments will use an in vitro model of the human BBB. developed in this laboratory, to directly measure the effects of MCP-1 and MlP-la on monocyte transendothelial migration. The next series of studies will utilize both this model and isolated human brain microvessels to investigate whether these chemokines are transported paracellularly or transcellularly across the specialized brain microvascular endothelium. Subsequent investigations will determine whether recognized receptors for these chemokines exist on the abluminal microvascular surface, and,if so, to examine their role in chemokine transport. The final experiments will illuminate microvascular responses to chemokine stimulation, e.g..altered adhesion molecule expression and permeability, which could support leukocyte infiltration. This study will be the first to characterize the interactions of MCP-1 and MlP-la at the BBB. Furthermore, in appreciation of the critical role of MCP-1 and MlP-la in CNS inflammation, these experimentswill greatly aid in comprehending pathogenetic mechanisms involved in this condition, and in developing novel therapeutics to antagonize chemokine actions in neuroinflammatorydisease. PERFORMANCE SITE ========================================Section End===========================================