Mechanisms of fibrin action in multiple sclerosis

描述(由申请人提供)：在多发性硬化症(MS)的脱髓鞘斑块中，纤维蛋白和纤维蛋白降解产物(FDPs)在神经系统内的广泛沉积被很好地记录下来。鉴于纤维蛋白、FDPs及其细胞表面受体在炎症反应和组织重塑/修复中发挥作用，它们是炎性脱髓鞘的关键决定因素。我们的主要假设是，纤维蛋白利用神经系统细胞的受体在神经系统病理中发挥有害作用。我们的初步研究结果表明：1.药物耗竭纤维蛋白逆转自身免疫性脑脊髓炎(EAE)的复发性瘫痪并改善炎性脱髓鞘；2.纤维蛋白在体内和体外均可诱导小胶质细胞活化；3.阻断Mac-1(CD11b/CD18)纤维蛋白受体可改善纤维蛋白在体外诱导的小胶质细胞活化。我们的最终目标是设计一种治疗纤维蛋白衰竭的新方法，潜在地应用于多发性硬化症和其他与纤维蛋白沉积相关的神经系统疾病。在这项赠款提案中，我们将确定多发性硬化症动物模型中纤维蛋白原基因缺失或纤维蛋白原Mac-1结合位点基因消除的影响(目标1)。我们将研究纤维蛋白/Mac-1相互作用在小胶质细胞激活功能中的作用，如增殖、吞噬和细胞因子释放(目标2和3)。两种已知抗凝剂的治疗效果以及一种特定的纤维蛋白/Mac-1抑制剂的疗效将在两种MS动物模型中进行评估(AIM 4)。这项拟议的研究将为止血因子在炎性脱髓鞘发病机制中的作用提供细胞和分子上的定义，并将在MS动物模型中确定抗凝剂的治疗效果。识别神经系统中的纤维蛋白作用受体可能最终阐明治疗MS的新治疗策略。

DESCRIPTION (provided by applicant): The widespread deposition of fibrin and fibrin degradation products (FDPs) within the nervous system is well documented in demyelinating plaques in Multiple Sclerosis (MS). Given that fibrin, FDPs and their cell surface receptors play a role in both the inflammatory response and tissue remodeling/repair, they are prime candidates to be critical determinants of inflammatory demyelination. Our major hypothesis is that fibrin utilizes receptors of nervous system cells to exert deleterious effects in nervous system pathology. Our preliminary data demonstrate that: 1. Pharmacologic depletion of fibrin reverses relapsing paralysis and ameliorates inflammatory demyelination in autoimmune encephalomyelitis (EAE); 2. Fibrin induces microglia activation both in vivo and in vitro; 3. Blocking the Mac-1 (CD11b/CD18) fibrin receptor ameliorates fibrin-induced microglia activation in vitro. Our ultimate goal is to design a novel therapeutic approach for fibrin depletion with potential application in MS and other neurologic diseases associated with fibrin deposition. In this grant proposal we will determine the impact of genetic depletion of fibrinogen or genetic elimination of the fibrinogen Mac-1 binding site in animal models for MS (Aim 1). We will examine the involvement of fibrin/Mac-1 interactions in functions of microglia activation, such as proliferation, phagocytosis and cytokine release (Aims 2 and 3). The therapeutic efficacy of 2 known anticoagulants, as well as the efficacy of a specific fibrin/Mac-1 inhibitor will be assessed in 2 animal models of MS (Aim 4). The proposed studies will provide a cellular and molecular definition of the role of hemostatic factors in the pathogenesis of inflammatory demyelination and will determine the therapeutic efficacy of anticoagulants in animal models for MS. Identifying the receptors of fibrin actions in the nervous system could ultimately illuminate new therapeutic strategies for the treatment of MS.