Pathogenesis of Nerve Injury: Role of Matrix Metalloproteinases

描述(由申请人提供)： 项目概述这个外周神经损伤研究项目旨在为神经损伤提供机械性见解和有针对性的治疗策略。在我们的VA优秀奖项目过程中，我们发现基质金属蛋白酶(MMPs)是一种细胞外蛋白水解酶家族，作为神经免疫激活、脱髓鞘、神经元死亡和坐骨神经损伤后神经病理性疼痛的关键调节因子，被用作成功的哺乳动物神经元再生模型。不同的基质金属蛋白酶家族成员在神经损伤过程中表现出不同的功能，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。例如，基质金属蛋白酶-9是一个早期基因家族成员，它在损伤后仅在神经中表达高达300倍，仅在损伤后几小时内表达。基质金属蛋白酶-9刺激雪旺细胞(SC)营养信号(如ErbB和IGF-1)，导致细胞外信号调节激酶(ERK)的持续激活，调节SC有丝分裂和髓鞘蛋白的合成。基质金属蛋白酶-9基因缺失显示出显著的神经保护作用，减少了免疫细胞对损伤神经的渗透，并显著改变了髓鞘蛋白的周转。使用特定的、广谱的MMPI治疗在减少痛性触觉过敏症(即正常无害刺激引起的疼痛)、保护髓鞘免受退化以及改善神经元和神经胶质细胞存活方面非常有效。我们的实验数据也证明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。本项目的目的是利用体外、体外和体内的一系列方法，确定单个MMPs在周围神经退行性变级联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。导致神经变性和神经病理性疼痛的最常见原因在退伍军人管理局患者最常见的健康问题清单上，包括糖尿病、酒精中毒、中风和脊髓损伤。该方案旨在加快神经退行性疾病的新疗法的开发和实施。 公共卫生相关性： 目前退伍军人管理局患者的人口概况显示，该国近三分之一的人口(超过6000万人)是退伍军人、家属或享有退伍军人医疗保健系统特权的已故退伍军人的遗属。神经退行性疾病的流行病学研究表明，VA患者群体处于神经元损伤、感觉功能丧失和衰弱性神经病理性疼痛的特殊风险中。这些原因被列在VA患者最常见的健康问题清单上，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(MMPs)来进行分子干预。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.