Mechanisms of fibrin action in multiple sclerosis

点击翻译按钮获取中文摘要

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.