Myelin Autoantigens in Neuropathic Pain

神经性疼痛中的髓磷脂自身抗原

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

我们提出了无害机械刺激（例如轻触）或轻微空气的病理疼痛运动（被定义为机械性异常尼亚）代表女性的自身免疫性疾病。从概念上讲这种难治性慢性疼痛表型的新观点是我们更新应用的首要论文。最近的半功雌性和雄性啮齿动物的机械性异常性。但是，这种性的机制二态现象是晦涩的。我们开创性的数据表明，已知的自动抗原髓磷脂碱性蛋白质（MBP）是机械性异常性二态性的机械钥匙。我们建议这样做任何在机械敏感Aβ型纤维上对髓鞘鞘的物理损伤会导致蛋白水解通常避免免疫监视的加密MBP的解放。辣椒编码 MBP的中央（84-104）区域（MBP84-104）产生直接，强大和持久的对轻触觉的超敏反应（Aβ 纤维介导的）但不是热（C纤维介导的）刺激。需要配置的组氨酸（H）-89站点才能 MBP84-104的细胞内转运和夸张活性。使用生化和分子工具，包括质量光谱法，RNA测序，生物信息学，结构建模和野生型免疫接种，突变体和控制PETIDE，结合严格的药物，神经病理和行为分析，我们确定了一组MBP84-104相互作用器和下游信号传导因子促进女性（和/或保护男性免受异常性疾病的发展）。这些MBP84-104相关的引线与在这里，在疼痛电路中建立的角色，例如X染色体印迹基因白介素6，在这里与A有关脂质，免疫和雌激素受体信号通路的主调节剂，肝X受体，这是新的疼痛场。通过我们在多产的合作中获得的独特，应计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的精确分子事件，导致性神经性疼痛中的二态性。我们希望我们的创新发现将促进概念的发展新型的镇痛疗法可用于慢性疼痛的难治类型。