Proteolysis of Myelin as a Source of Neuropathic Pain

髓磷脂的蛋白水解是神经性疼痛的根源

基本信息

批准号：
9315285
负责人：
VERONICA SHUBAYEV
金额：
$ 10万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-30 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9315285
关键词：
Action Potentials Affect Analgesics Animals Antigen Presentation Antigen-Presenting Cells Antigens Behavior Behavioral Binding Biochemical Biochemistry Bioinformatics Blood-Nerve Barrier CD28 gene CD4 Positive T Lymphocytes Cell Culture Techniques Cell surface Cells Chronic Clone Cells Complex Data Databases Development Diagnostic Disease Doctor of Medicine Doctor of Philosophy Epitopes Event Exhibits Fiber Figs - dietary Gelatinase B Genes Glutamate Receptor Helper-Inducer T-Lymphocyte Homing Hyperalgesia Immune Immune response Immunodominant Antigens Immunodominant Epitopes Immunologic Monitoring Infiltration Inflammation Injection of therapeutic agent Injury Lead Lesion Light Locomotion MALDI-TOF Mass Spectrometry Major Histocompatibility Complex Matrix Metalloproteinases Mechanics Mediating Medical Research Molecular Myelin Myelin Basic Proteins Myelin Sheath N-Methyl-D-Aspartate Receptors Nerve Nervous system structure Neurobiology Neurons Nociception Nude Rats Pain Pathway interactions Peptides Peripheral Peripheral Nerves Peripheral nerve injury Pharmacology Production Proteolysis Proteome RNA Splicing Ranvier&apos s Nodes Reaction Recovery Research Design Resources Role Schwann Cells Sensory Shelter facility Signal Pathway Signal Transduction Sodium Sodium Channel Solid Source Spinal Spinal Cord Stimulus Synapses System T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes Tactile Therapeutic Touch sensation Variant Veronica afferent nerve allodynia antigen processing base bead chip cell motility chronic pain collagenase 3 cytokine glial activation inflammatory pain inhibitor/antagonist injured injury and repair innovation macrophage mechanical allodynia molecular domain myelination nerve injury neuroinflammation neurotransmission novel painful neuropathy prevent programs receptor repaired response sciatic nerve somatosensory synaptogenesis tool trafficking voltage

Action Potentials Affect Analgesics Animals Antigen Presentation Antigen-Presenting Cells Antigens Behavior Behavioral Binding Biochemical Biochemistry Bioinformatics Blood-Nerve Barrier CD28 gene CD4 Positive T Lymphocytes Cell Culture Techniques Cell surface Cells Chronic Clone Cells Complex Data Databases Development Diagnostic Disease Doctor of Medicine Doctor of Philosophy Epitopes Event Exhibits Fiber Figs - dietary Gelatinase B Genes Glutamate Receptor Helper-Inducer T-Lymphocyte Homing Hyperalgesia Immune Immune response Immunodominant Antigens Immunodominant Epitopes Immunologic Monitoring Infiltration Inflammation Injection of therapeutic agent Injury Lead Lesion Light Locomotion MALDI-TOF Mass Spectrometry Major Histocompatibility Complex Matrix Metalloproteinases Mechanics Mediating Medical Research Molecular Myelin Myelin Basic Proteins Myelin Sheath N-Methyl-D-Aspartate Receptors Nerve Nervous system structure Neurobiology Neurons Nociception Nude Rats Pain Pathway interactions Peptides Peripheral Peripheral Nerves Peripheral nerve injury Pharmacology Production Proteolysis Proteome RNA Splicing Ranvier&apos s Nodes Reaction Recovery Research Design Resources Role Schwann Cells Sensory Shelter facility Signal Pathway Signal Transduction Sodium Sodium Channel Solid Source Spinal Spinal Cord Stimulus Synapses System T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes Tactile Therapeutic Touch sensation Variant Veronica afferent nerve allodynia antigen processing base bead chip cell motility chronic pain collagenase 3 cytokine glial activation inflammatory pain inhibitor/antagonist injured injury and repair innovation macrophage mechanical allodynia molecular domain myelination nerve injury neuroinflammation neurotransmission novel painful neuropathy prevent programs receptor repaired response sciatic nerve somatosensory synaptogenesis tool trafficking voltage

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项目摘要

DESCRIPTION (provided by applicant): Neuropathic pain (NP) is 'pain arising as a direct consequence of a lesion or disease affecting the somatosensory nervous system' that has certain features of a neuroimmune disorder. In response to peripheral nerve damage, T helper (Th) lymphocyte trafficking and induction of major histocompatibility complex (MHC) II (essential to the capture and antigen presentation for Th cell recognition) in the injured nerve and the segmental spinal cord are 'necessary and sufficient' for the development of NP. MHCII has been implicated in differential induction of NP but not inflammatory pain, but the antigens and the processes of their formation remain elusive. Our groundbreaking program centers on the organizing thesis that immunodominant antigens, formed in damaged myelinated nerves, are at the source of low-threshold mechanical hyperpathia. Touch is signaled by non-nociceptive large myelinated (Ab) afferents, which after injury begin interpreting light touch as devastating pain (mechanical allodynia). Our cutting-edge preliminary data have determined a fundamentally novel mechanism explaining this phenomenon: selective proteolysis of myelin basic protein (MBP) by matrix metalloproteinases (MMPs) releases the cryptic immunodominant epitopes, MBP84-104 and MBP69-86, normally sheltered from immunosurveillance. We clearly demonstrate that immunodominant MBP peptides produce robust allodynia upon injection into intact nerve. An intriguing finding is that endogenous immunodominant MBP69-86 epitope co-localizes with MHCII in antigen-presenting Schwann cells of the injured nerve, in close proximity to the action potential-generating nodes of Ranvier. Using state-of-the-art biochemical and molecular tools (e.g. Illumina BeadChip gene arrays, MALDI-TOF mass spectrometry, Ingenuity, NextBio, GeneGo and proprietary MMP substrate database) and fundamental (neuropathological, behavioral, systems) approaches, we will characterize the T cell-dependent and -independent actions of MBP residues in nociception (Aim 1). The molecular domains of myelinated fibers responsible for MBP action in T cell homing and locomotion, and also, the receptors for MBP residues in nerve will be determined (Aim 2). Importantly, we determined that voltage gated sodium channel expression and the spinal release of a glutamate receptor subunit depend on MMP activity. The concluding focus of the proposal are the novel catalytic and non- catalytic MMP targets in regulating T cell trafficking and integration into the spinal neuro-glial signaling network, facilitating maladaptive central plasticity and aberrant neuroimmune synaptogenesis (Aim 3). This multi- disciplinary program merges the leading expertise and utmost resources in biochemistry of metalloproteolysis (Alex Strongin, Ph.D., Sanford-Burnham Medical Research Inst.), neurobiology of MMPs in peripheral myelination and neuroinflammation (Veronica Shubayev, M.D., UCSD), and pain pathways (Tony Yaksh, Ph.D., UCSD) with innovative study designs, which we believe are bound to transform our mechanistic understanding diagnostic and therapeutic practices predicting and preventing the transition to the NP state.

描述（由申请人提供）：神经性疼痛（NP）是“疼痛是由于影响体感神经系统的病变或疾病的直接结果，它具有神经免疫性疾病的某些特征。为了响应周围神经损伤，T助手（Th）淋巴细胞运输和主要组织相容性复合物（MHC）II（MHC）II（对于受伤的神经的捕获和抗原表现至关重要）和段性脊髓中的段落脊髓是“必要的，并且足够的NP开发”。 MHCII与NP的差异诱导有关，但没有炎症性疼痛，但是抗原和形成过程仍然难以捉摸。我们的开创性计划集中在组织论文中，即在受损的骨髓神经中形成的免疫主导抗原是低阈值机械性超速pathia的来源。触摸是由非伤害性的大髓的（AB）传入发出的，后者在受伤后开始将轻触摸解释为毁灭性疼痛（机械性异常性痛）。我们的尖端初步数据已经确定了一种从根本上说明这种现象的新机制：通过基质金属蛋白酶（MMPS）对髓磷脂碱性蛋白（MBP）的选择性蛋白质解释，它释放了隐秘的免疫力学表现，MBP84-104和MBP69-86，正常遮盖的MBP84-104和MBP69-86。我们清楚地表明，免疫主导的MBP肽在注射到完整的神经后会产生健壮的异常性疾病。一个有趣的发现是，内源性免疫主导MBP69-86表位与受伤神经的抗原呈现的schwann细胞共定位，与RANVIER的动作潜在生成节点相近。使用最先进的生物化学和分子工具（例如Illumina beadchip基因阵列，Maldi-TOF质谱，Ingenity，Nextbio，Nextbio，Genego，Genego和专有MMP MMP底物数据库）和基本病理学（神经病理学，行为，系统）的方法（我们将在细胞依赖性和依赖性（MB）方面取决于-Indectimigent（我们将依赖于M.Indepente） 1）。髓鞘纤维的分子结构域，负责T细胞归巢和运动中MBP作用，以及神经中MBP残基的受体（AIM 2）。重要的是，我们确定电压门控钠通道表达和谷氨酸受体亚基的脊柱释放取决于MMP活性。该提案的总结重点是在调节T细胞运输和整合到脊髓神经膜信号网络中的新型催化和非催化MMP靶标，促进了适应不良的中枢性可塑性和异常的神经免疫性突触（AIM 3）。该多学科计划将金属蛋白解析生物化学的主要专业知识和最大资源融合在一起（Alex Strongin，Ph.D.，Sanford-Burnham Medical Research Inst。），MMP的神经生物学外周血髓鞘和神经炎症中的神经生物学（Veronica Shubayev，M.D.创新的研究设计，我们认为这必定会改变我们的机械理解诊断和治疗实践，从而预测并防止过渡到NP状态。