Chemokines and Chemokine Receptors in Multiple Sclerosis

这个项目的总体目标是深入了解多发性硬化症(MS)中的细胞贩运和激活。我们专注于趋化因子和趋化因子受体，它们在中枢神经系统(CNS)中的浸润性白细胞和小胶质细胞上都有表达。我们的一般假设是趋化因子及其受体有助于确定炎性中枢神经系统浸润物的特异性。最近，抗白细胞整合素抗体的成功临床试验证实了阻断白细胞转运以抑制MS炎症的方法，小分子趋化因子受体拮抗剂治疗MS的II期试验正在进行中。因此，阐明趋化因子及其受体在多发性硬化症发生发展过程中的作用，明确合适的治疗靶点变得越来越重要。的具体目标 这一竞争更新将集中在以下关键问题上：第一，趋化因子如何调节血液传播的白细胞最初进入脑脊液和中枢神经系统实质？其次，趋化因子如何控制血液来源的白细胞和小胶质细胞在炎症实质内的迁移和激活？第三，趋化因子及其受体在进展性多发性硬化症的局部化炎症反应中的作用是什么？我们建议的研究将详细研究趋化因子及其受体在MS不同形式和不同阶段的发病机制中的作用，并将确定趋化因子受体拮抗剂的治疗靶点。

The overall goal of this project is to gain insight into cell trafficking and activation in multiple sclerosis (MS). We focus on chemokines and chemokine receptors, which are expressed both on infiltrating leukocytes and microglia in the central nervous system (CNS). Our general hypothesis is that chemokines and their receptors help determine the specific character of inflammatory CNS infiltrates. Recently, successful clinical trials of anti-leukointegrin antibodies validated the approach of blocking leukocyte trafficking to suppress inflammation in MS and phase II trials of small molecule chemokine receptor antagonists for treating MS are in progress. Therefore, it is increasingly important to delineate how chemokines and their receptors function during the evolution of MS, and clarify appropriate treatment targets. The Specific Aims of this competing renewal will focus on the following key issues: First, how do chemokines regulate initial entry of blood-borne leukocytes into the CSF and CNS parenchyma? Second, how do chemokines govern migration and activation of blood-derived leukocytes and microglia within the inflamed parenchyma ? Third, what is the role of chemokines and their receptors in the compartmentalized inflammatory reaction of progressive MS? Our proposed research will examine in detail the roles of chemokines and their receptors in the pathogenesis of MS in its varied forms and phases, and will identify targets for treatment with chemokine receptor antagonists.