Pathogenesis of Nerve Injury: Role of Matrix Metalloproteinases

项目摘要 这项周围神经损伤研究计划旨在提供机制的见解和有针对性的治疗 神经元损伤的策略。在退伍军人管理局优秀奖项目中，我们发现了矩阵 金属蛋白酶（MMPs），细胞外蛋白酶家族，作为神经免疫激活的关键调节剂， 脱髓鞘，神经元死亡和坐骨神经损伤后的神经性疼痛，用作成功的哺乳动物 神经元再生模型。单个MMP家族成员在神经生长过程中显示出不同的功能。 损伤，提示选择性MMP抑制剂（MMPi）治疗靶向干预的重要性。为 例如，MMP-9是一种早期基因家族成员，其仅在损伤后的神经中表达， 300-就在几个小时后MMP-9刺激雪旺细胞（SC）营养（例如ErbB和IGF-1）信号传导 导致细胞外信号调节激酶（ERK）的持续激活和SC有丝分裂的调节， 髓鞘蛋白质合成。MMP-9基因缺失显示出显着的神经保护作用，减少免疫细胞 浸润到损伤的神经和髓鞘蛋白周转的显著变化。具体的，广泛的治疗- 谱MMPi在减轻疼痛性触觉异常性疼痛（即，正常无害的疼痛 刺激），保护髓鞘免于降解和改善神经元和神经胶质存活。我们的试点数据还 证明了其在促进大鼠坐骨神经挤压后神经再生速率方面的前景。这个目标 计划是建立在启动和发展的过程中，个别MMPs的作用， 神经退行性级联在周围神经，利用一系列在体外，离体和体内的方法。它 为VA患者的神经退行性疾病和感觉丧失制定治疗策略。的 神经变性和神经性疼痛的最常见原因是在VA患者的列表中， 常见的健康问题，包括糖尿病、酗酒、中风和脊髓损伤。本项目旨在 加快神经退行性疾病新疗法的开发和实施。

Project Summary This peripheral nerve injury research program aims to provide mechanistic insights and targeted therapeutic strategies for neuronal damage. In the course of our VA Merit Award program we discovered matrix metalloproteinases (MMPs), a family of exracellular proteases, as key modulators of neuroimmune activation, demyelination, neuronal death and neuropathic pain after sciatic nerve injury, used as a successful mammalian model of neuronal regeneration. Individual MMP family members display differential functions during nerve damage, suggesting the importance of selective MMP inhibitor (MMPi) therapy for targeted intervention. For example, MMP-9 is an early-gene family member, that is expressed in nerve exclusively after injury by up to a 300-fold and only hours after insult. MMP-9 stimulates Schwann cell (SC) trophic (e.g. ErbB and IGF-1) signaling leading to sustained activation of extracellular signal-regulated kinase (ERK) and regulation of SC mitosis and myelin protein synthesis. MMP-9 gene deletion demonstrate remarkable neuroprotection, reduced immune cell infiltration into the injured nerve and notable changes to myelin protein turnover. Therapy with specific, broad- spectrum MMPi was highly effective in reducing painful tactile allodynia (i.e., pain from normally innocous stimuli), in protecting myelin from degradation and improving neuronal and glial survival. Our pilot data also demonstrates its promise in promoting the rate of nerve regrowth after rat sciatic nerve crush. The goal of this program is to establish the roles of individual MMPs in the processes of initiation and development of neurodegenerative cascades in peripheral nerve, utilizing a series of in vitro, ex vivo and in vivo approaches. It offers to develop therapeutic strategies for neurodegenerative diseases and sensory loss in VA patients. The most common causes of neurodegeneration and neuropathic pain are on the list of the VA patients most common health concerns, including diabetes, alcoholism, stroke and spinal cord injury. This porgram is designed to expedite the development and implementation of novel therapies to neurodegenerative diseases.