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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：
10469339
负责人：
VERONICA SHUBAYEV
金额：
$ 74.7万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469339
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 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 therapy innovation male mechanical allodynia mechanical stimulus 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。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A monoclonal antibody interferes with TIMP-2 binding and incapacitates the MMP-2-activating function of multifunctional, pro-tumorigenic MMP-14/MT1-MMP.

单克隆抗体会干扰 TIMP-2 结合，并使多功能促肿瘤 MMP-14/MT1-MMP 的 MMP-2 激活功能丧失能力。

DOI：
10.1038/oncsis.2013.44
发表时间：
2013
期刊：
Oncogenesis
影响因子：
6.2
作者：
Shiryaev,SA;Remacle,AG;Golubkov,VS;Ingvarsen,S;Porse,A;Behrendt,N;Cieplak,P;Strongin,AY
通讯作者：
Strongin,AY

Peptide Sequence Region That is Essential for the Interactions of the Enterotoxigenic Bacteroides fragilis Metalloproteinase II with E-cadherin.

对于产肠毒素脆弱拟杆菌金属蛋白酶 II 与 E-钙粘蛋白相互作用至关重要的肽序列区域。