Chemokines and Chemokine Receptors in Multiple Sclerosis

多发性硬化症中的趋化因子和趋化因子受体

• 批准号: 6876990
• 负责人: Richard M. Ransohoff
• 金额: $ 27.13万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6876990
• 关键词: T lymphocyte; astrocytes; blood brain barrier; cell migration; chemokine; chemokine receptor; clinical research; human tissue; inflammation; leukocyte activation /transformation; leukocytes; microglia; monocyte; multiple sclerosis; pathologic process; receptor expression

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.

该项目的总体目标是深入了解多发性硬化症（MS）的细胞运输和激活。我们专注于趋化因子和趋化因子受体，这是在浸润性白细胞和小胶质细胞在中枢神经系统（CNS）的表达。我们的一般假设是，趋化因子及其受体有助于确定炎性CNS浸润的特异性。最近，抗白细胞整联蛋白抗体的成功临床试验验证了阻断白细胞运输以抑制MS炎症的方法，并且用于治疗MS的小分子趋化因子受体拮抗剂的II期试验正在进行中。因此，阐明趋化因子及其受体在MS演变过程中的作用，并阐明适当的治疗靶点变得越来越重要。的具体目标 这种竞争性更新将集中在以下关键问题上：首先，趋化因子如何调节血液携带的白细胞最初进入CSF和CNS实质？第二，趋化因子如何调控炎症实质内血液来源的白细胞和小胶质细胞的迁移和活化？第三，趋化因子及其受体在进展性MS的区室化炎症反应中的作用是什么？我们提出的研究将详细研究趋化因子及其受体在MS发病机制中的作用，以其不同的形式和阶段，并将确定与趋化因子受体拮抗剂治疗的目标。