Pathogenesis of Nerve Injury: Role of Matrix Metalloproteinases

项目摘要 此外周神经损伤研究计划旨在提供机械性见解和靶向治疗 神经元损伤的策略。在我们的VA优秀奖项目过程中，我们发现了矩阵 金属蛋白酶(MMPs)是一类细胞外蛋白水解酶，作为神经免疫激活的关键调节因子， 坐骨神经损伤后脱髓鞘、神经元死亡和神经病理性疼痛，作为一种成功的哺乳动物 神经元再生模型。单个基质金属蛋白酶家族成员在神经过程中表现出不同的功能 损伤，提示选择性基质金属蛋白酶抑制剂(MMPI)治疗对于靶向干预的重要性。为 例如，MMP9是一个早期基因家族成员，它在损伤后仅在神经中表达，最高可达 300倍，而且只在侮辱后几个小时。基质金属蛋白酶-9刺激雪旺细胞(SC)营养(如ErbB和IGF-1)信号 导致细胞外信号调节激酶(ERK)的持续激活，并调节SC有丝分裂和 髓鞘蛋白合成。基质金属蛋白酶-9基因缺失显示出显著的神经保护作用，免疫细胞减少 渗入受损神经，髓鞘蛋白周转有明显变化。用具体的，广泛的-治疗 SPECTRUM MMPI在减少痛性触觉过敏症(即正常无害的疼痛)方面非常有效 刺激)，保护髓鞘免受降解，提高神经元和神经胶质细胞的存活率。我们的试点数据也 展示了它在促进大鼠坐骨神经挤压后神经再生的速度方面的前景。这样做的目的是 计划是确定单个MMP在启动和发展过程中的作用 利用一系列体外、体外和体内方法，周围神经退行性变发生级联反应。它 为退伍军人管理局患者的神经退行性疾病和感觉丧失制定治疗策略。这个 最常见的神经变性和神经病理性疼痛的原因在退伍军人管理局患者名单上最多 常见的健康问题，包括糖尿病、酒精中毒、中风和脊髓损伤。这个节目是专门设计的 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.