Pathogenesis of Nerve Injury: Role of Matrix Metalloproteinases

描述（由申请人提供）： 该周围神经损伤研究计划旨在为神经元损伤提供机制见解和有针对性的治疗策略。在我们的VA优异奖计划的过程中，我们发现了基质金属蛋白酶（MMPs），一个细胞外蛋白酶家族，作为坐骨神经损伤后神经免疫激活，脱髓鞘，神经元死亡和神经性疼痛的关键调节剂，用作神经元再生的成功哺乳动物模型。单个MMP家族成员在神经损伤期间显示出不同的功能，这表明选择性MMP抑制剂（MMPi）治疗对于靶向干预的重要性。例如，MMP-9是早期基因家族成员，其仅在损伤后的神经中表达高达300倍，并且仅在损伤后数小时表达。MMP-9刺激施万细胞（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）的持续活化和SC有丝分裂和髓鞘蛋白合成的调节。MMP-9基因缺失显示出显著的神经保护作用，减少了免疫细胞浸润到损伤的神经中，并显着改变髓鞘蛋白质周转。用特异性广谱MMPi治疗在减少疼痛性触觉异常性疼痛（即，正常无害刺激引起的疼痛），保护髓鞘免于降解并改善神经元和神经胶质存活。我们的试验数据也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。本项目的目标是利用一系列体外、离体和体内方法，建立单个MMPs在外周神经神经退行性级联反应的启动和发展过程中的作用。它为VA患者的神经退行性疾病和感觉丧失提供了治疗策略。神经变性和神经性疼痛的最常见原因是VA患者最常见的健康问题，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。 公共卫生相关性： 退伍军人事务部患者目前的人口统计资料显示，全国近三分之一的人口（超过6000万人）是退伍军人，家属或已故退伍军人的幸存者，他们享有退伍军人事务部医疗保健系统的特权。神经退行性疾病的流行病学表明，VA患者人群存在神经元损伤、感觉功能丧失和使人衰弱的神经性疼痛的特殊风险。这些原因是VA患者最常见的健康问题，包括创伤，脊髓损伤，糖尿病和酒精中毒，并可能通过抑制基质金属蛋白酶（MMPs）进行分子干预。通过临床前研究了解神经元损伤的机制对于加快神经退行性疾病新疗法的开发和实施至关重要。

DESCRIPTION (provided by applicant): 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 demonstrates 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. PUBLIC HEALTH RELEVANCE: The current demographic profile of the VA patients shows that almost one-third of the nation's population (over 60 million people) are veterans, dependents or survivors of deceased veterans who have privileges of the VA Healthcare System. The epidemiology of neurodegenerative diseases suggests that the VA patient population is at special risk of neuronal damage, loss of sensory function and debilitating neuropathic pain. The causes are on the list of the VA patients' most common health concerns, including trauma, spinal cord injury, diabetes and alcoholism and may be amenable to the molecular intervention by inhibition on matrix metalloproteainses (MMPs). Understanding the mechanisms of neuronal damage through preclinical studies is critical to expediteing the development and implementation of novel therapies to neurodegenerative diseases.