Pathogenesis of Nerve Injury: Role of Matrix Metalloproteinases

神经损伤的发病机制：基质金属蛋白酶的作用

• 批准号: 8397543
• 负责人: VERONICA SHUBAYEV
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397543
• 关键词: Adhesives; Alcoholism; Algorithms; Apoptosis; Award; Axon; Axotomy; Basal lamina; Calcium; Caliber; Cell Death; Cell Surface Receptors; Cell Survival; Cell physiology; Cell surface; Cells; Cessation of life; Coculture Techniques; Collagen Type IV; Crush Injury; Data; Demyelinations; Deoxyuridine; Deposition; Development; Diabetes Mellitus; Distal; Ensure; Environment; Enzyme-Linked Immunosorbent Assay; Epidemiology; ErbB4 gene; Family; Family member; Fiber; Funding; Gelatinase A; Gelatinase B; Gelatinases; Gene Deletion; Gene Family; Glial Fibrillary Acidic Protein; Goals; Growth; Health; Healthcare Systems; Hour; Immune; In Vitro; Individual; Infiltration; Inflammatory; Inhibition of Matrix Metalloproteinases Pathway; Injury; Insulin-Like Growth Factor I; Intervention; Knowledge; Ligands; Link; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Membrane; Messenger RNA; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Mitosis; Modeling; Molecular; Mus; Myelin; Myelin Associated Glycoprotein; Myelin Basic Proteins; Myelin Proteins; Natural regeneration; Nerve; Nerve Crush; Nerve Degeneration; Nerve Fibers; Nerve Regeneration; Neuraxis; Neuregulin 1; Neurites; Neurodegenerative Disorders; Neuroglia; Neurons; Oligodendroglia; Pain; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Peritoneal Macrophages; Phagocytosis; Phenotype; Phosphotransferases; Play; Population; Process; Property; Protein Biosynthesis; Proteolysis; Rattus; Receptor Protein-Tyrosine Kinases; Recovery of Function; Recruitment Activity; Regulation; Research; Risk; Rodent; Role; Schwann Cells; Sensory; Series; Signal Transduction; Site; Small Interfering RNA; Speed; Spinal Ganglia; Spinal cord injury; Stimulus; Stroke; Stromelysin 1; Survivors; System; Tactile; Testing; Therapeutic; Time; Trauma; Tube; Tumor Necrosis Factor-alpha; Veterans; Wallerian Degeneration; Western Blotting; Wild Type Mouse; Work; Zinc; allodynia; axon regeneration; base; cell type; chronic pain; clinically relevant; collagenase; design; extracellular; growth inhibitory proteins; human TNF protein; improved; in vivo; inhibitor/antagonist; injured; insight; interest; knockout gene; mRNA Differential Displays; macrophage; nerve injury; neurite growth; neuroinflammation; neuronal growth; neuronal survival; neuroprotection; novel; painful neuropathy; patient population; preclinical study; programs; protein degradation; public health relevance; receptor; regenerative; remyelination; repaired; sciatic nerve; success; therapeutic target

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.

描述（由申请人提供）： 项目摘要 该周围神经损伤研究项目旨在为神经元损伤提供机制见解和针对性治疗策略。在我们的 VA 优异奖计划过程中，我们发现基质金属蛋白酶 (MMP)，一种细胞外蛋白酶家族，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，可用作成功的哺乳动物神经元模型再生。各个 MMP 家族成员在神经损伤期间表现出不同的功能，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 是一种早期基因家族成员，仅在损伤后的神经中表达，表达量在损伤后仅数小时内表达量高达 300 倍。 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) 持续激活并调节 SC 有丝分裂和髓磷脂蛋白合成。 MMP-9 基因缺失表现出显着的神经保护作用、减少了免疫细胞浸润到受损神经以及髓鞘蛋白周转的显着变化。特异性、广谱 MMPi 治疗在减轻疼痛性触觉异常性疼痛（即正常无害刺激引起的疼痛）、保护髓磷脂免于降解以及改善神经元和神经胶质存活方面非常有效。我们的试验数据还证明了它在促进大鼠坐骨神经挤压后神经再生速率方面的前景。该计划的目标是利用一系列体外、离体和体内方法，确定单个 MMP 在周围神经神经退行性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制定治疗策略。神经退行性变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。该计划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： 目前 VA 患者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 VA 医疗保健系统的特权。神经退行性疾病的流行病学表明，VA 患者群体面临神经元损伤、感觉功能丧失和神经病理性疼痛的特殊风险。 VA 患者最常见的健康问题包括外伤、脊髓损伤、糖尿病和酗酒等，并且可能需要通过抑制基质金属蛋白酶 (MMP) 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。