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.

我们认为，病理性疼痛是由无害的机械刺激（例如轻触或轻微空气）引起的。运动（定义为机械性异常性疼痛）代表女性的一种自身免疫性疾病。这种难治性慢性疼痛表型的新观点是我们最近更新申请的首要论点。开创性的工作涉及适应性免疫/T 细胞和先天免疫系统/小胶质细胞的发育分别发生在雌性和雄性啮齿动物中的机械异常性疼痛。我们的突破性数据表明，一种已知的自身抗原，髓磷脂，二态性现象是模糊的。碱性蛋白（MBP）是机械性异常性疼痛中性别二态性的机制关键。对机械敏感的 Aβ 传入纤维上的髓鞘的任何（包括物理）损伤都会导致蛋白水解释放通常不受免疫监视的神秘 MBP 肽。 MBP 的中央 (84-104) 区域 (MBP84-104) 对轻触产生直接、强烈和持久的超敏反应 (Aβ 纤维介导的）而非热（C 纤维介导的）刺激需要保守的组氨酸 (H)-89 位点。使用生化和分子工具，包括 MBP84-104 的细胞内运输和镇痛活性。野生型的质谱分析、RNA 测序、生物信息学、结构建模和免疫捕获，突变肽和对照肽，结合严格的药理学、神经病理学和行为学分析后，我们确定了一组 MBP84-104 相互作用因子和下游信号因子，促进这些与 MBP84-104 相关的线索与女性（和/或保护男性免受）异常性疼痛的发展有关。疼痛回路中已确定的作用，例如 X 染色体印记基因白细胞介素 6，在这里与脂质、免疫和雌激素受体信号通路的主调节器，肝脏 X 受体，这是新发现的凭借我们独特的、积累的工具集和在多产合作中获得的严格数据。由 PI、Veronica Shubayev（UCSD）、Tony Yaksh（UCSD）和 Alex Strongin（SBP）组成的团队，我们的目标是识别神经、背根神经节和脊髓中导致性行为的精确分子事件我们期望我们的创新发现将促进概念上的发展。适用于难治性慢性疼痛的新型镇痛疗法。