Pathogenesis of Nerve Injury: Role of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1)

神经损伤的发病机制：金属蛋白酶组织抑制剂 1 (TIMP-1) 的作用

• 批准号: 10456102
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456102
• 关键词: Absence of pain sensation; American; Analgesics; Behavior; Behavioral; Binding; Biological; Cell Nucleus; Cells; Choristoma; Chronic; Clinical; Clinical Research; Cutaneous; Cyclic AMP; Data; Development; Diagnostic; Economic Burden; Emotional; Endopeptidases; Epigenetic Process; Exhibits; Family; Female; Genes; Germ Cells; Goals; Histone H3; Human; Immune; Inflammatory; Inhibition of Matrix Metalloproteinases Pathway; Injury; Leg; Limb structure; Link; Mass Spectrum Analysis; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Medical; Metabolic; Methylation; Morphine; Myelin; Natural regeneration; Nerve; Nervous System Trauma; Neurons; Nuclear; Opioid; Pain; Pain management; Pathogenesis; Patients; Pattern; Peptide Hydrolases; Peripheral Nervous System; Pharmacology; Phase; Protein Isoforms; Proteins; Proteolysis; Recombinants; Regenerative capacity; Regulation; Reporting; Research; Role; Schwann Cells; Sensory; Sex Chromosomes; Source; Spinal Ganglia; TIMP1 gene; Technology; Therapeutic; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinases; Tissues; Transcript; Translating; Translational Research; Trauma; Variant; Vertebral column; Veterans; Work; X Chromosome; X Inactivation; base; chronic pain; combat; combat wound; cost; disability; enzyme replacement therapy; extracellular; foot; fundamental research; gene therapy; genomic locus; human tissue; in silico; injured; innovation; limb injury; macrophage; male; multidisciplinary; nerve injury; nerve repair; neuroinflammation; painful neuropathy; personalized medicine; prevent; programs; protein H(3); regenerative; repaired; response; response to injury; sciatic nerve; sex; sexual dimorphism; systems research; tool; trafficking; transcriptome sequencing; transcriptomics

Extremity trauma causing peripheral nervous system (PNS) injury accounts for the majority of combat wounds. Despite high regenerative capacity of the PNS, patients develop severe neuropathic pain, not amenable to analgesic therapies. The congressional Opioids and STOP Initiative Act of 2017 calls to “expand, intensify, and coordinate fundamental, translational, and clinical research” on pain and develop new non-addictive pain treatments. In addition to physical and emotional disability, chronic pain costs the U.S. over $ 600 billion every year. Over 65% of American Veterans report pain, with severe pain 40% greater in Veterans than non- Veterans. Our unbiased transcriptomics study identified Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) among the top-10 induced (out of thousands regulated) genes in painful PNS injury. The main function of TIMP-1 is inhibition of the matrix metalloproteinase (MMP) family of extracellular proteases. In the framework of this VA Merit program, we have pioneered the study of the MMP/TIMP axis in PNS injury and pain regulation. This renewal application centers on our second unbiased finding: TIMP-1 is an X-chromosome-linked gene, exhibiting polymorphic, aberrant and sex-dependent transcript isoforms in painful PNS injury. Our data strongly suggest that TIMP-1 is an analgesic, pro-survival and regenerative factor induced in the PNS in response to injury. However, expression of polymorphic, aberrant TIMP-1 transcript variants, potentially resulting in dysfunctional gene or protein products, predisposes to chronic pain development. With our innovative tools and concepts, groundbreaking data and strong track record in MMP/TIMP and PNS research, we aim to study cellular and subcellular, including nuclear patterns of TIMP-1 distribution, interactors and functions in PNS injury (Aim 1). We will then identify sex-specific, aberrant, transcript variants of TIMP-1 gene arising due to sexually dimorphic (X chromosome inactivation in females) and monomorphic (universal in both sexes) epigenetic abnormalities (Aim 2). As polymorphic TIMP-1 variants occur in humans, we expect our findings will swiftly translate into medical epigenetic diagnostics of pain states in a clinical setting. Finally we aim to develop targeted TIMP-1 gene therapy in PNS injury and pain (Aim 3). This program employs multidisciplinary state-of-the-art (e.g. RNA-seq, SMRT-BS, BioID, ChiP) technologies and fundamental neuropathological and behavioral approaches to study PNS injury and pain. We anticipate our program will make a major impact on pain diagnostics and development of non-addictive analgesics.

导致周围神经系统（PNS）损伤的四肢创伤占战伤的大部分。 尽管 PNS 具有很高的再生能力，但患者仍会出现严重的神经性疼痛，无法接受治疗。 2017 年议会阿片类药物和戒断倡议法案呼吁“扩大、加强和 协调基础、转化和临床研究” 治疗疼痛并开发新的非成瘾性疼痛 治疗。 除了身体和情感残疾之外，慢性疼痛还给美国造成了超过 10 美元的损失 每人6000亿 超过 65% 的美国退伍军人报告疼痛，其中退伍军人的剧烈疼痛比非退伍军人高 40%。 退伍军人。 我们的公正转录组学研究发现金属蛋白酶组织抑制剂-1 (TIMP-1) 引起疼痛的 PNS 损伤的前 10 个诱导基因（数千个受调节基因） TIMP-1 的主要功能是。 在此 VA 的框架内抑制细胞外蛋白酶的基质金属蛋白酶 (MMP) 家族。 优异计划，我们率先研究了 MMP/TIMP 轴在 PNS 损伤和疼痛调节中的作用。 更新申请以我们的第二个公正发现为中心：TIMP-1 是一个 X 染色体连锁基因， 在痛苦的 PNS 损伤中表现出多态性、异常和性别依赖性转录亚型。 我们的数据强烈表明 TIMP-1 是 PNS 中诱导的镇痛、促生存和再生因子 然而，多态性、异常的 TIMP-1 转录变体的表达可能会发生变化。 导致基因或蛋白质产物功能失调，容易导致慢性疼痛。 创新的工具和概念、突破性的数据以及 MMP/TIMP 和 PNS 研究方面的良好记录， 我们的目标是研究细胞和亚细胞，包括 TIMP-1 分布的核模式、相互作用因子和 然后我们将鉴定 TIMP-1 基因的性别特异性、异常转录变体。 由于性二态性（女性 X 染色体失活）和单态性（男女通用）而产生 由于多态性 TIMP-1 变异发生在人类中，我们期望我们的表观遗传异常。 研究结果将很快转化为临床环境中疼痛状态的医学表观遗传学诊断。 旨在开发针对 PNS 损伤和疼痛的靶向 TIMP-1 基因疗法（目标 3）。 该项目采用多学科最先进的技术（例如 RNA-seq、SMRT-BS、BioID、ChiP） 以及研究三七总皂甙损伤和疼痛的基本神经病理学和行为方法。 我们的计划将对疼痛诊断和非成瘾性镇痛药的开发产生重大影响。