Mechanisms of fibrin action in multiple sclerosis

纤维蛋白在多发性硬化症中的作用机制

• 批准号: 8089235
• 负责人: Katerina Akassoglou
• 金额: $ 41.04万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8089235
• 关键词: Alzheimer' s Disease; Ancrod; Animal Model; Anticoagulants; Anticoagulation; Applications Grants; Binding; Binding Sites; Blood - brain barrier anatomy; Blood coagulation; Cell Surface Receptors; Cells; Cessation of life; Chronic; Coagulants; Data; Demyelinations; Deposition; Disease; Doctor of Philosophy; Encephalomyelitis; Event; Experimental Autoimmune Encephalomyelitis; Fibrin; Fibrin split products; Fibrinogen; Genes; Genetic; Goals; Hemorrhage; Hemostatic Agents; ITGAM gene; ITGB2 gene; In Vitro; Inflammatory; Inflammatory Response; Injury; Knock-in Mouse; Knock-out; Low-Molecular-Weight Heparin; Macrophage-1 Antigen; Mediating; Microglia; Modeling; Molecular; Multiple Sclerosis; Mus; Mutant Strains Mice; Mutation; Natural regeneration; Nervous system structure; Neurodegenerative Disorders; Neurologic; Neurons; Paralysed; Pathogenesis; Pathology; Peptide Hydrolases; Peptides; Phagocytosis; Play; Process; Receptor Signaling; Relapse; Research Personnel; Risk; Role; Signal Pathway; Signal Transduction; Site; Snake Venoms; System; Testing; Therapeutic; Therapeutic Effect; Tissues; Treatment Efficacy; Warfarin; Work; cytokine; design; efficacy testing; fibrin receptor; in vivo; inhibitor/antagonist; neuroinflammation; novel therapeutic intervention; novel therapeutics; receptor; repaired; treatment strategy

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.

描述（由申请人提供）：纤维蛋白和纤维蛋白降解产物（FDP）在神经系统内的广泛沉积在多发性硬化症（MS）的脱髓鞘斑块中得到充分记录。鉴于纤维蛋白、FDP 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，它们是炎症脱髓鞘的关键决定因素的主要候选者。我们的主要假设是纤维蛋白利用神经系统细胞的受体对神经系统病理学产生有害影响。我们的初步数据表明： 1. 纤维蛋白的药理学消耗可逆转复发性麻痹并改善自身免疫性脑脊髓炎 (EAE) 中的炎症性脱髓鞘； 2. 纤维蛋白在体内和体外均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诱导的体外小胶质细胞活化。我们的最终目标是设计一种新的纤维蛋白消耗治疗方法，并有望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。在此拨款提案中，我们将确定多发性硬化症动物模型中纤维蛋白原基因耗竭或纤维蛋白原 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参与，例如增殖、吞噬作用和细胞因子释放（目标 2 和 3）。将在 2 种 MS 动物模型中评估 2 种已知抗凝剂的治疗功效以及特定纤维蛋白/Mac-1 抑制剂的功效（目标 4）。拟议的研究将为止血因子在炎症脱髓鞘发病机制中的作用提供细胞和分子定义，并将确定抗凝剂在多发性硬化症动物模型中的治疗效果。识别神经系统中纤维蛋白作用的受体最终可能会阐明治疗多发性硬化症的新治疗策略。