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: 7796957
• 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 2013-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796957
• 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）： 项目摘要该外围神经损伤研究计划旨在为神经元损害提供机械见解和有针对性的治疗策略。在我们的VA功绩奖计划的过程中，我们发现了一个杂细胞蛋白酶的基质金属蛋白酶（MMP），是神经免疫激活，脱髓鞘，神经元死亡和神经性神经疼痛后的关键调节剂，用于成功的哺乳动物模型的神经元模型。单个MMP家族成员在神经损伤过程中显示出不同的功能，这表明选择性MMP抑制剂（MMPI）治疗对靶向干预的重要性。例如，MMP-9是一个早期基因的家庭成员，在受伤后仅在300倍之后，仅在侮辱后仅几个小时就在神经中表达。 MMP-9刺激Schwann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）的持续激活以及SC有丝分裂和髓磷脂蛋白合成的调节。 MMP-9基因缺失表现出显着的神经保护作用，免疫细胞浸润降低到受伤的神经中，并显着变化髓磷脂蛋白质的转化。特异性，广谱MMPI的治疗在减少疼痛的触觉异常性痛（即，正常无辜刺激的疼痛）方面非常有效，可以保护髓磷脂免受降解和改善神经元和神经胶质生存。我们的飞行员数据还证明了其在大鼠坐骨神经挤压后促进神经再生速率方面的希望。该程序的目的是利用一系列体外，体内和体内方法来确定单个MMP在周围神经中神经退行性级联反应的过程中的作用。它提供了为VA患者制定神经退行性疾病和感觉丧失的治疗策略。神经退行性和神经性疼痛的最常见原因在于VA患者最常见的健康问题，包括糖尿病，酒精中毒，中风和脊髓损伤。该遗传旨在加快对神经退行性疾病的新疗法的开发和实施。 公共卫生相关性： VA患者的当前人口统计信息表明，该国近三分之一的人口（超过6000万人）是有特权VA医疗保健系统的退伍军人，家属或幸存者。神经退行性疾病的流行病学表明，VA患者人群有神经元损害，感觉功能丧失和使神经性疼痛的特殊风险。原因是VA患者最常见的健康问题的列表，包括创伤，脊髓损伤，糖尿病和酒精中毒，可以通过抑制基质金属蛋白（MMPS）来适应分子干预。通过临床前研究了解神经元损害的机制对于加快对神经退行性疾病的新疗法的开发和实施至关重要。