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: 10622245
• 负责人: Aubin Moutal
• 金额: $ 32.09万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-14 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622245
• 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，影响普通人群的5-10％， 由于人口老龄化，预计将来会变得更加普遍。虽然镇痛药是 可用，这种类型的疼痛特别抵抗我们当前的治疗策略，使患者几乎没有 选项。此外，这些药物会引起严重的副作用。当然，这对个人来说是巨大的使人衰弱的 负面影响他们的生活质量。此外，它具有重大的经济影响（治疗成本， 休假的时间）是需要解决医疗服务的负担。结果，有一个 迫切需要开发新的靶向良好的疗法来治疗神经性疼痛。一个障碍有 一直缺乏从基础科学发现到诊所的翻译。在这里，我们的目的是通过使用 患者样本以增强我们的基础研究的相关性。现在已经被神经免疫了 相互作用有助于异常疼痛状态，而在研究的方面相对较为疼痛状态。 人类自身抗体。抗CV2自身抗体的靶向称为Collapsin响应介质的蛋白质 蛋白5（CRMP5）与患者的神经性疼痛有关。 CRMP5是一个研究的闭神经 蛋白质在发育中的大脑中高度表达。在成年人中，大脑不存在CRMP5的表达 保留在脊髓中存在的感觉神经元，神经和突触中。在神经性疼痛中，CRMP5 表达在脊髓的突触后部位降低，而Glun2b的水平是一个亚基。 NMDA受体和一种新型的CRMP5结合蛋白增加了。使用患者的自身抗体和大鼠 神经性疼痛的模型，我们将检验以下假设：CRMP5功能的破坏是异常性异常的基础 抗CV2自身免疫性神经病和神经性疼痛。 AIM 1将研究感觉的改变 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。因此，我们将破译抗CV2的作用部位 自身抗体会产生异常性抗体。 AIM 2将着重阐明CRMP5的前后突触后功能 在脊柱神经传递和神经性疼痛中。我们将探讨丢失CRMP5法规的新颖想法 glun2b的神经性疼痛中异常动物症的基础。该提议结合了新型生化和 逆转CRMP5（抗CV2）自身免疫性的临床发现的功能方法 异常性症询问CRMP5如何导致神经性疼痛。新型治疗的识别 慢性疼痛的目标是一个令人兴奋的结果，可以实现未来的治疗性发育。