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）：