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: 8195911
• 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/8195911
• 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

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.

项目摘要 该外围神经损伤研究计划旨在提供机械洞察力和有针对性的治疗性 神经元损害的策略。在我们发现矩阵的VA优异奖计划的过程中 金属蛋白酶（MMP）是一个杂细胞蛋白酶的家族，作为神经免疫激活的关键调节剂， 坐骨神经损伤后的脱髓鞘，神经元死亡和神经性疼痛，用作成功的哺乳动物 神经元再生的模型。单个MMP家庭成员在神经期间显示出差异功能 损害，表明选择性MMP抑制剂（MMPI）疗法对靶向干预的重要性。为了 例如，MMP-9是一个早期基因家庭成员，在受伤后仅在神经中表达 侮辱后仅300倍。 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。 MMP-9基因缺失表现出显着的神经保护，免疫细胞降低 渗透到受伤的神经中，并显着变化髓磷脂蛋白更新。特定，广泛的治疗 Spectrum MMPI在减少疼痛的触觉异常性异常（即通常无辜的疼痛）方面非常有效 刺激），保护髓磷脂免受降解并改善神经元和神经胶质生存。我们的飞行员数据也 证明了其在大鼠坐骨神经挤压后促进神经再生速率的希望。目标的目标 计划是确定单个MMP在启动和开发过程中的作用 外周神经中的神经退行性级联反应，利用一系列体外，体内和体内方法。它 为VA患者制定神经退行性疾病和感觉丧失的治疗策略的提议。这 神经退行性和神经性疼痛的最常见原因在VA患者列表中。 常见的健康问题，包括糖尿病，酒精中语，中风和脊髓损伤。这个孔设计是设计的 加快对神经退行性疾病的新疗法的开发和实施。