The role of CASPR2 in regulating sensory neuronal excitability and chronic pain

CASPR2在调节感觉神经元兴奋性和慢性疼痛中的作用

• 批准号: MR/M02394X/1
• 负责人: David Bennett
• 金额: $ 44.02万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM02394X%2F1
• 关键词: role; CASPR2; regulating; sensory; neuronal

Pain alerts the body to actual or potential tissue damage and thereby helps to prevent any initial or further injury. In the case where tissue is damaged the sensation of pain is enhanced in an effort to protect the injured area and speed the recovery process. Therefore pain is a useful sensation albeit an unpleasant one. However pain can become maladaptive, persisting beyond its usefulness and becoming debilitating for the sufferer. This type of pain, which persists for months and in some cases years, is termed chronic pain and affects 1 in 5 adults. It has major economic repercussions due to treatment costs and time spent off work and this is in spite of current analgesic use. In addition to a lack of efficacy current analgesics also cause severe side-effects. We have new data to suggest that contactin associated protein 2 (CASPR2), a protein expressed within the sensory nervous system, can regulate pain sensibility. Autoantibodies to this protein have recently been associated with neuropathic pain in patients. The main aim of this project will be to determine the role of CASPR2 in both acute and chronic pain states. We will develop an animal model in order to understand how CASPR2 autoantibodies cause chronic pain. Furthermore levels of CASPR2 fall after nerve injury. We will determine if this contributes to neuropathic pain through its known interactions with potassium channels which have an important role in regulating neuronal excitability. Our aim is to define how CASPR2 alters function within the sensory nervous system to better target current therapeutics in patients with autoantibodies to this protein but also to potentially develop novel therapeutics for the treatment of neuropathic pain.

疼痛提醒身体注意实际或潜在的组织损伤，从而有助于防止任何初始或进一步的损伤。在组织受损的情况下，疼痛的感觉会增强，以保护受伤部位并加速恢复过程。因此，疼痛是一种有用的感觉，尽管是一种不愉快的感觉。然而，疼痛可能变得适应不良，持续超过其有用性，并成为患者衰弱。这种类型的疼痛持续数月，在某些情况下持续数年，被称为慢性疼痛，影响五分之一的成年人。由于治疗费用和下班时间，它具有重大的经济影响，尽管目前使用止痛药。除了缺乏功效之外，目前的镇痛剂还引起严重的副作用。我们有新的数据表明，接触相关蛋白2（CASPR2），一种在感觉神经系统内表达的蛋白质，可以调节疼痛敏感性。这种蛋白质的自身抗体最近与患者的神经性疼痛有关。该项目的主要目的是确定CASPR2在急性和慢性疼痛状态中的作用。我们将开发一种动物模型，以了解CASPR2自身抗体如何引起慢性疼痛。此外，CASPR2水平在神经损伤后下降。我们将确定这是否有助于神经性疼痛，通过其已知的相互作用与钾通道，在调节神经元兴奋性的重要作用。我们的目标是确定CASPR2如何改变感觉神经系统内的功能，以更好地靶向具有该蛋白自身抗体的患者的当前治疗方法，同时也可能开发用于治疗神经性疼痛的新型治疗方法。

项目成果

Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability

免疫或遗传介导的 CASPR2 破坏会因初级传入兴奋性增强而导致疼痛过敏

• DOI: 10.5167/uzh-150090
• 发表时间: 2018
• 作者: Dawes, John M

Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero.

• DOI: 10.1007/s00401-017-1751-5
• 发表时间: 2017-10
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Coutinho E;Menassa DA;Jacobson L;West SJ;Domingos J;Moloney TC;Lang B;Harrison PJ;Bennett DLH;Bannerman D;Vincent A
• 通讯作者: Vincent A

Leucine-Rich Glioma-Inactivated 1 versus Contactin-Associated Protein-like 2 Antibody Neuropathic Pain: Clinical and Biological Comparisons.

• DOI: 10.1002/ana.26189
• 发表时间: 2021-10
• 期刊: Annals of neurology
• 影响因子: 11.2
• 作者: Ramanathan S;Tseng M;Davies AJ;Uy CE;Paneva S;Mgbachi VC;Michael S;Varley JA;Binks S;Themistocleous AC;Fehmi J;Anziska Y;Soni A;Hofer M;Waters P;Brilot F;Dale RC;Dawes J;Rinaldi S;Bennett DL;Irani SR
• 通讯作者: Irani SR

Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability.

• DOI: 10.1016/j.neuron.2018.01.033
• 发表时间: 2018-02-21
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Dawes JM;Weir GA;Middleton SJ;Patel R;Chisholm KI;Pettingill P;Peck LJ;Sheridan J;Shakir A;Jacobson L;Gutierrez-Mecinas M;Galino J;Walcher J;Kühnemund J;Kuehn H;Sanna MD;Lang B;Clark AJ;Themistocleous AC;Iwagaki N;West SJ;Werynska K;Carroll L;Trendafilova T;Menassa DA;Giannoccaro MP;Coutinho E;Cervellini I;Tewari D;Buckley C;Leite MI;Wildner H;Zeilhofer HU;Peles E;Todd AJ;McMahon SB;Dickenson AH;Lewin GR;Vincent A;Bennett DL
• 通讯作者: Bennett DL

Autism Spectrum Disorders: Multiple Routes to, and Multiple Consequences of, Abnormal Synaptic Function and Connectivity.

• DOI: 10.1177/1073858420921378
• 发表时间: 2021-03
• 期刊: The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
• 作者: Carroll L;Braeutigam S;Dawes JM;Krsnik Z;Kostovic I;Coutinho E;Dewing JM;Horton CA;Gomez-Nicola D;Menassa DA
• 通讯作者: Menassa DA