Myelin Autoantigens in Neuropathic Pain

神经性疼痛中的髓磷脂自身抗原

• 批准号: 10210252
• 负责人: VERONICA SHUBAYEV
• 金额: $ 72.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10210252
• 关键词: Adaptive Immune System; Agonist; Air Movements; Amyloid beta-Protein; Analgesics; Anti-Inflammatory Agents; Antigen-Antibody Complex; Attenuated; Autoantigens; Autoimmune; Autoimmune Diseases; Behavioral; Biochemical; Bioinformatics; C Fiber; Calcium; Calcium Signaling; Collaborations; Data; Development; Disease; Electrophysiology (science); Epitopes; Estrogen Receptors; Estrogens; Event; Female; Fiber; Fostering; Funding; Gap Junctions; Histidine; Homing; Hyperalgesia; Hypersensitivity; IL6 gene; ITPR1 gene; Immune; Immune response; Immunologic Receptors; Immunologic Surveillance; In Vitro; Injections; Injury; Innate Immune System; Inositol; Interleukin-6; Interneurons; Intracellular Transport; LXRalpha protein; Light; Link; Lipids; Liver; Liver X Receptor; Mass Spectrum Analysis; Mechanical Stimulation; Mechanics; Mediating; Membrane Lipids; Membrane Microdomains; Microglia; Molecular; Myelin; Myelin Basic Proteins; Myelin Sheath; Nerve; Nerve Tissue; Neurons; Nociception; Pain; Painless; Pathologic; Pathway Analysis; Peptides; Persistent pain; Pharmacology; Phenotype; Protein Biochemistry; Proteins; Ranvier' s Nodes; Rattus; Receptor Cell; Receptor Signaling; Refractory; Resistance; Reticulum; Rodent; Role; Seminal; Signal Pathway; Signal Transduction; Site; Spinal; Spinal Cord; Spinal Ganglia; Stimulus; Stress; Structural Models; T-Lymphocyte; Tactile; Testing; Therapeutic; Touch sensation; Traumatic injury; Veronica; Work; X Chromosome; afferent nerve; allodynia; chronic constriction injury; chronic pain; imprint; in vivo; inhibitor/antagonist; innovation; male; mechanical allodynia; multidisciplinary; mutant; nerve injury; neuroinflammation; neuronal cell body; novel; painful neuropathy; prevent; programs; protein folding; protein kinase C gamma; receptor; sciatic nerve; sexual dimorphism; somatosensory; tool; transcriptome sequencing; tripolyphosphate; vibration

We propose that pathological pain from innocuous mechanical stimulation such as light touch or slight air movement (defined as mechanical allodynia) represents an autoimmune disorder in females. This conceptually new view of this refractory chronic pain phenotype is the overarching thesis of our renewal application. Recent seminal work implicates adaptive immune/T cells and innate immune system/microglia in the development of mechanical allodynia in female and male rodents, respectively. However, the mechanisms of this sexual dimorphism phenomenon are obscure. Our groundbreaking data suggests that a known auto-antigen, myelin basic protein (MBP), holds the mechanistic key to sexual dimorphism in mechanical allodynia. We suggest that any, including physical, damage to myelin sheath on mechanosensitive Aβ-afferent fibers results in proteolytic liberation of cryptic MBP peptides normally sheltered from immunosurveillance. The peptide encoding the central (84-104) region of MBP (MBP84-104) produces direct, robust and lasting hypersensitivity to light touch (Aβ fiber-mediated) but not thermal (C fiber-mediated) stimulation. The conserved histidine (H)-89 site is required to intracellular transport and the algesic activity of MBP84-104. Using biochemical and molecular tools, including mass-spectrometry, RNA-sequencing, bioinformatics, structural modeling, and immunocapture of wildtype, mutant and control peptides, combined with rigorous pharmacological, neuropathological, and behavioral analyses, we identified a cluster of the MBP84-104 interactors and downstream signaling factors promoting in females (and/or protecting males from) the development of allodynia. These MBP84-104-related leads with the established roles in pain circuitry, such as the X-chromosome imprinted gene interleukin 6, are here linked to a master-regulator of lipid, immune and estrogen receptor signaling pathways, liver X receptor, which is new to the pain field. With our unique, accrued toolset and rigorous data obtained in a prolific collaboration among the teams of the PI, Veronica Shubayev (UCSD) with Tony Yaksh (UCSD) and Alex Strongin (SBP), we aim to identify the precise molecular events in nerve, dorsal root ganglia and spinal cord leading to the sexual dimorphism in neuropathic pain. We expect our innovative findings will foster the development of conceptually novel analgesic therapeutics useful in refractory types of chronic pain.

我们认为，病理性疼痛来自无害的机械刺激，如轻触或轻微的空气 运动（定义为机械性异常性疼痛）代表女性的自身免疫性疾病。这在概念上 这种难治性慢性疼痛表型的新观点是我们更新申请的首要论点。最近 开创性的工作涉及适应性免疫/T细胞和先天免疫系统/小胶质细胞在发展中的作用， 机械性异常性疼痛，分别在女性和男性啮齿动物。然而，这种性行为的机制 二态现象不明显。我们的突破性数据表明一种已知的自身抗原髓鞘 碱性蛋白（MBP），掌握着机械异常性疼痛中两性异形的机制关键。我们建议 对机械敏感性Aβ-传入纤维上髓鞘的任何损伤，包括物理损伤，都会导致蛋白水解， 释放隐藏的MBP肽通常不受免疫监视。编码所述多肽的肽 MBP的中央（84-104）区（MBP 84 -104）产生直接、强烈和持久的轻触超敏反应（Aβ 纤维介导的）而不是热（C纤维介导的）刺激。保守的组氨酸（H）-89位点是必需的， 细胞内转运和MBP 84 -104的镇痛活性。使用生物化学和分子工具，包括 质谱、RNA测序、生物信息学、结构建模和野生型的免疫捕获， 突变体和对照肽，结合严格的药理学，神经病理学和行为学， 分析，我们确定了一组MBP 84 -104相互作用因子和下游信号传导因子， 雌性（和/或保护雄性免于）异常性疼痛的发展。这些MBP 84 -104相关电极导线 在疼痛回路中的既定作用，如X染色体印记基因白细胞介素6，在这里与一个 主要调节脂质，免疫和雌激素受体信号传导途径，肝X受体，这是新的， 疼痛领域。凭借我们独特的、累积的工具集和严格的数据， PI团队，Veronica Shubayev（UCSD）与Tony Yaksh（UCSD）和Alex Strongin（SBP），我们的目标是 确定神经，背根神经节和脊髓中导致性行为的精确分子事件 神经性疼痛的二型性。我们希望我们的创新发现将促进概念上的发展， 用于难治性类型慢性疼痛的新的镇痛治疗剂。