INTERACTIONS OF FIBRINOGEN WITH p75NTR

描述(申请人提供)：纤维蛋白是一种血液衍生蛋白，在中风、多发性硬化症(MS)和脑胶质母细胞瘤等与血管破裂相关的疾病后沉积在神经系统中。我们之前在遗传或药物上缺乏纤维蛋白原的小鼠上进行的研究表明，在多发性硬化的动物模型中，纤维蛋白抑制周围神经再生并加剧中枢神经系统的炎性脱髓鞘。我们的长期目标是确定纤维蛋白用于诱导神经系统病理的分子和细胞界面。 这一建议的具体假设是，纤维蛋白与p75神经营养素受体(P75NTR)相互作用，介导其在神经系统中的作用。我们的假设是基于以下观察结果：1：纤维蛋白原及其衍生物直接与p75NTR结合，从而可能直接调节受体功能；2.p75NTR在体内的表达调节纤维蛋白及其衍生物在神经系统中的生物利用度。3.纤维蛋白原及其降解产物通过p75NTR介导多种生存反应。 基于这些观察，这项建议的实验重点是对p75NTR与纤维蛋白原相互作用的生化、体内和体外分析。其具体目的是：1.建立p75NTR与纤维蛋白原及其衍生物的生化相互作用；2：确定纤维蛋白原对三叉神经节和中枢神经系统p75NTR表达细胞类型的生物学效应；3：确定p75NTR/纤维蛋白相互作用在神经再生和炎性脱髓鞘中的作用。由于p75NTR在成人神经系统对损伤的反应是上调的，识别p75NTR与纤维蛋白的分子相互作用可能为以血管损伤、内皮细胞激活和组织修复能力降低为特征的各种疾病的药物干预提供损伤特异性靶点。

DESCRIPTION (provided by applicant): Fibrin is a blood-derived protein deposited in the nervous system after disease associated with vasculature rupture; such as stroke, multiple sclerosis (MS) and brain glioblastomas. Our previous studies in mice genetically or pharmacologically deficient in fibrinogen demonstrated that fibrin inhibits peripheral nerve regeneration and exacerbates inflammatory demyelination in the central nervous system in an animal model for MS. Our long term goal is to identify the molecular and cellular interface that fibrin utilizes to induce nervous system pathology. The specific hypothesis of this proposal is that fibrin interacts with the p75 neurotrophin receptor (p75NTR) to mediate its effects in the nervous system. Our hypothesis is based on the observations that 1: Fibrinogen and its derivatives directly bind to p75NTR and thus may directly modulate receptor function; 2. p75NTR expression in vivo regulates the bioavailability of fibrin and its derivatives in the nervous system. 3. Fibrinogen and its degradation products mediate diverse survival responses via p75NTR. Based on these observations, the experimental focus of this proposal is on the biochemical, in vivo and in vitro analysis of the p75NTR interactions with fibrinogen. The specific aims are to: 1. Establish the biochemical interactions of p75NTR with fibrinogen and its derivatives, 2: Determine the biological effects induced by fibrin(ogen) in p75NTR - expressing cell types in the PNS and CNS and 3: Establish the contribution of p75NTR / fibrin interactions in nerve regeneration and inflammatory demyelination. Since p75NTR is upregulated in the adult nervous system in response to injury, identifying the molecular interactions of p75NTR with fibrin could potentially provide injury-specific targets for pharmacological intervention in a variety of diseases characterized by vascular damage, endothelial cell activation and decreased capacity for tissue repair.