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

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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