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

基本信息

  • 批准号:
    10094769
  • 负责人:
  • 金额:
    $ 36.89万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
摘要 神经性疼痛是常见的神经系统疾病,影响5-10%的一般人群, 由于人口老龄化,预计在未来会变得更加普遍。虽然止痛药 这种类型的疼痛对我们目前的治疗策略特别有抵抗力, 选项.此外,这些药物会引起严重的副作用。当然,这对个人来说是非常虚弱的, 对他们的生活质量产生负面影响。此外,它具有显著的经济后果(治疗成本, 下班时间),并且是需要解决的医疗保健服务的负担。因此,有一个 迫切需要开发新的更好的靶向治疗神经性疼痛的疗法。一个障碍是, 缺乏从基础科学发现到临床的转化。在这里,我们的目标是通过使用 患者样本,以提高我们的基础研究的相关性。现在人们普遍认为,神经免疫 相互作用导致异常疼痛状态,一个相对研究不足的方面是通过作用 人类自身抗体抗CV 2自身抗体靶向一种称为抗CV 2应答介体的蛋白质 蛋白质5(CRMP 5),并且与患者的神经性疼痛相关。CRMP 5是一种研究不足的肿瘤神经 在发育中的大脑中高度表达的蛋白质。在成年人中,CRMP 5表达在大脑中缺失, 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,CRMP 5 在脊髓中突触后位点表达减少,而GluN 2B的亚单位GluN 2B的水平降低。 NMDA受体和一种新的CRMP 5结合蛋白增加。利用病人的自身抗体和老鼠 在神经病理性疼痛模型中,我们将检验CRMP 5功能的破坏是异常性疼痛的基础这一假设。 抗CV 2自身免疫性神经病和神经性疼痛。目的1:研究感觉神经元的变化 抗CV 2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。有了这个,我们将破译抗CV 2的作用位点, 自身抗体产生异常性疼痛。目的2将着重阐明CRMP 5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CRMP 5调控缺失的新观点, GluN 2B的表达是神经病理性疼痛中异常性疼痛的基础。该提案使用了新型生物化学和 功能性方法来逆转CRMP 5(抗CV 2)自身免疫引起的临床发现 研究CRMP 5如何促进神经性疼痛。一种新型治疗药物的鉴定 慢性疼痛靶向治疗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。

项目成果

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Aubin Moutal其他文献

Aubin Moutal的其他文献

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{{ truncateString('Aubin Moutal', 18)}}的其他基金

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
  • 财政年份:
    2022
  • 资助金额:
    $ 36.89万
  • 项目类别:
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:
    10553262
  • 财政年份:
    2022
  • 资助金额:
    $ 36.89万
  • 项目类别:
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:
    10321941
  • 财政年份:
    2021
  • 资助金额:
    $ 36.89万
  • 项目类别:

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