Anti-CV2 autoantibodies unmask a CRMP5/GluN2B pain signaling hub

抗 CV2 自身抗体揭示了 CRMP5/GluN2B 疼痛信号中枢

• 批准号: 10094769
• 负责人: Aubin Moutal
• 金额: $ 36.89万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10094769
• 关键词: Address; Adult; Affect; Afferent Neurons; Amantadine; Analgesics; Animals; Antibodies; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Responses; Autoimmunity; Axon; Basic Science; Binding; Binding Proteins; Biochemical; Brain; Categories; Cells; Clinic; Clinical; Conflict (Psychology); Depressed mood; Development; Disease; Down-Regulation; Economics; Electrophysiology (science); Event; Future; General Population; Glutamates; Human; Immune response; Individual; Investigation; Link; Malignant Neoplasms; Mechanics; Mediator of activation protein; Methods; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Names; Nerve; Neuroimmune; Neurologic; Neurons; Neuropathy; Nociception; Outcome; Pain; Pain management; Paraneoplastic Syndromes; Pathologic; Patients; Peripheral; Peripheral nerve injury; Pharmaceutical Preparations; Physiological; Polyradiculoneuropathy; Proteins; Quality of life; Rattus; Receptor Signaling; Regulation; Research; Resistance; Role; Sampling; Semaphorin-3A; Sensory; Site; Slice; Spinal; Spinal Cord; Stimulus; Synapses; Synaptic Transmission; Syndrome; Testing; Thymoma; Time; Translating; Translations; Treatment Cost; Up-Regulation; Work; aging population; allodynia; alpha Tubulin; behavior test; chronic neuropathic pain; chronic pain; clinically relevant; depressive behavior; experimental study; health care service; in vivo; innovation; lung small cell carcinoma; mechanical allodynia; negative affect; nervous system disorder; neurotransmission; neurotransmitter release; new therapeutic target; novel; pain signal; painful neuropathy; research clinical testing; response; side effect; synaptic function; targeted treatment; therapeutic development; therapeutic target; trafficking; treatment strategy; tumor

Abstract Neuropathic pain is common neurological disorder affecting between 5-10% of the general population and predicted to become more common in the future because of the aging population. Although analgesics are available, this type of pain is particularly resistant to our current treatment strategies leaving patients with few options. In addition, these drugs cause severe side effects. This is of course hugely debilitating for individuals, negatively affecting their quality of life. Furthermore, it has significant economic ramifications (treatment costs, time spent off work) and is a burden on healthcare services that needs to be addressed. As a result, there is a pressing need to develop new better-targeted therapies for the treatment of neuropathic pain. One obstacle has been the lack of translation from basic science findings into the clinic. Here, we aim to address this by using patient samples to enhance the relevance of our basic research. It is now well accepted that neuroimmune interactions contribute to abnormal pain states and one relatively under studied aspect of is through the action of human autoantibodies. The anti-CV2 autoantibodies target a protein called collapsin response mediator protein 5 (CRMP5) and are associated with neuropathic pain in patients. CRMP5 is an understudied onconeural protein highly expressed in the developing brain. In adults, CRMP5 expression is absent from the brain but retained in sensory neurons, nerves and synapses present in the spinal cord. In neuropathic pain, CRMP5 expression is decreased at post-synaptic sites in the spinal cord, while the levels of GluN2B, a subunit of the NMDA receptor, and a novel CRMP5 binding protein, is increased. Using patients' autoantibodies and a rat model of neuropathic pain, we will test the hypothesis that disruption of CRMP5 functions underlies allodynia in anti-CV2 autoimmune neuropathy and in neuropathic pain. Aim 1 will investigate the alterations of sensory neurotransmission elicited by anti-CV2 autoantibodies. This will include a functional profiling of sensory neurons using whole cell and slice electrophysiology. With this we will decipher the site of action of anti-CV2 autoantibodies produce to allodynia. Aim 2 will focus on elucidating the pre- and post-synaptic function of CRMP5 in spinal neurotransmission and neuropathic pain. We will explore the novel idea that loss of CRMP5 regulation of GluN2B underlies allodynia in neuropathic pain. This proposal uses a combination of novel biochemical and functional methods to reverse-translate the clinical findings of CRMP5 (anti-CV2) auto-immunity causing allodynia to interrogate how CRMP5 can contribute to neuropathic pain. The identification of a novel therapeutic target for chronic pain is an exciting outcome with far reaching applications for future therapeutic development.

抽象的 神经性疼痛是常见的神经系统疾病，影响 5-10% 的普通人群 由于人口老龄化，预计未来将变得更加普遍。虽然止痛药是 可用的，这种类型的疼痛对我们目前的治疗策略特别有抵抗力，使患者几乎没有 选项。此外，这些药物会引起严重的副作用。这对个人来说当然是极大的削弱， 对他们的生活质量产生负面影响。此外，它还具有重大的经济影响（处理成本、 下班时间），并且是需要解决的医疗保健服务的负担。结果，有一个 迫切需要开发新的更有针对性的疗法来治疗神经性疼痛。一个障碍有 缺乏将基础科学发现转化为临床的问题。在这里，我们的目标是通过使用来解决这个问题 患者样本以增强我们基础研究的相关性。现在人们普遍认为神经免疫 相互作用会导致异常疼痛状态，其中一个相对未被研究的方面是通过动作 人类自身抗体。抗 CV2 自身抗体针对一种称为塌陷素反应介质的蛋白质 蛋白 5 (CRMP5) 与患者的神经性疼痛有关。 CRMP5 是一种尚未得到充分研究的神经 蛋白质在发育中的大脑中高度表达。在成人中，CRMP5 的表达在大脑中不存在，但 保留在脊髓中的感觉神经元、神经和突触中。在神经性疼痛中，CRMP5 脊髓突触后位点的表达降低，而 GluN2B（GluN2B 的一个亚基）的水平 NMDA 受体和一种新型 CRMP5 结合蛋白增加。使用患者的自身抗体和大鼠 在神经性疼痛模型中，我们将检验以下假设：CRMP5 功能的破坏是异常性疼痛的基础 抗 CV2 自身免疫性神经病和神经性疼痛。目标 1 将调查感官的改变 抗CV2自身抗体引起的神经传递。这将包括感觉神经元的功能分析 使用全细胞和切片电生理学。借此我们将破译抗 CV2 的作用位点 自身抗体会产生异常性疼痛。目标 2 将重点阐明 CRMP5 的突触前和突触后功能 脊髓神经传递和神经性疼痛。我们将探讨 CRMP5 调控丧失的新想法 GluN2B 的存在是神经性疼痛中异常性疼痛的基础。该提案结合了新型生化和 反向翻译 CRMP5（抗 CV2）自身免疫引起的临床结果的功能方法 异常性疼痛来探究 CRMP5 如何导致神经性疼痛。新型治疗方法的鉴定 慢性疼痛的目标是一个令人兴奋的结果，对未来的治疗发展具有深远的应用。