Investigating the role of Leucine rich, glioma inactivated 1 (LGI1) in regulating pain sensitivity

研究富含亮氨酸的神经胶质瘤失活 1 (LGI1) 在调节疼痛敏感性中的作用

• 批准号: MR/V003534/1
• 负责人: John Dawes
• 金额: $ 74.32万
• 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: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV003534%2F1
• 关键词: Investigating; role; Leucine; rich; glioma

Trauma to the nervous system or diseases such as diabetes can injure neurons involved in signalling pain resulting in them becoming over-active and triggering the unpleasant sensation of pain. This type of pain, termed neuropathic pain, is unpleasant, long lasting and results in a poor quality of life for the sufferer. Neuropathic pain is common affecting between 5-10% of people and will become more common with an aging population. Although analgesics are available, this type of pain is particularly resistant to our current treatment strategies leaving the patient with few options. In addition, these drugs cause severe side-effects. This is of course hugely debilitating for the individual, negatively impacting on their way of life. Furthermore, it has significant economic ramifications (treatment costs, time spent off work) and in general is a burden on healthcare services which 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 I aim to address this by using patient samples to enhance the clinical relevance of my research findings. Autoantibodies targeting Leucine-rich glioma inactivate 1 (LGI1) are associate with neuropathic pain in patients. This molecule interacts with potassium channels which are important for regulating the activity of neurons involved in signalling pain. I will use these antibodies to determine if disruption of LGI1 is the cause of pain in these patients and whether this protein is a common regulator of neuronal activity and therefore a viable target for the treatment of neuropathic pain as a whole. The aim of my research will be to first assess whether LGI1 impacts on pain sensation by using genetically altered mice which no longer express this protein and assessing their behaviour to sensory stimuli. Using these mice, I will measure the activity of their pain signalling neurons and determine if LGI1 impacts on this activity through its action on potassium channels. Through my collaborations I will obtain LGI1 autoantibodies (-Abs) from a number of patients with neuropathic pain. I will use these samples to develop an animal model in order to ascertain whether these antibodies are causal to the development of neuropathic pain. This study will not only shed light on the role of LGI1 in pain biology, but also autoantibodies as a mechanism to cause abnormal pain sensation in patients. I will use established animal models of nerve injury to better understand the role of LGI1 in the development of neuropathic pain. LGI1 is a secreted molecule and its presence increases/stabilises the activity of potassium channels (therefore decreasing the activity of pain signalling neurons). To test the therapeutic potential of modulating this system, I will create soluble LGI1 protein for use in animals to increase the availability of LGI1 to pain signalling neurons. Using preclinical models, I will test whether LGI1 treatment can reduce neuropathic pain behaviours in mice and therefore determine the analgesic potential of this approach.These findings will of course directly help neuropathic pain patients with LGI1-Abs, where treatments are already available to reduce antibody levels and could then be used specifically to treat pain. In the wider context, new treatments for neuropathic pain will have huge societal benefits and these findings can be applied to other persistent pain conditions.

神经系统的创伤或糖尿病等疾病会损害参与信号疼痛的神经元，从而导致它们变得过度活跃并触发不愉快的疼痛感觉。这种类型的疼痛称为神经性疼痛，令人不愉快，持久，导致患者的生活质量差。神经性疼痛很常见，在5-10％的人之间影响，随着人口老龄化会变得越来越普遍。尽管有镇痛药，但这种类型的疼痛特别抵抗我们当前的治疗策略，使患者几乎没有选择。另外，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，对他们的生活方式产生了负面影响。此外，它具有重大的经济影响（治疗成本，休假时间），通常是需要解决的医疗服务负担。结果，迫切需要开发新的更好的靶向疗法来治疗神经性疼痛。一个障碍是缺乏从基础科学发现到诊所的翻译。在这里，我的目的是通过使用患者样品来提高我的研究发现的临床相关性来解决这一问题。靶向富含亮氨酸的神经胶质瘤1（LGI1）的自身抗体与患者的神经性疼痛有关。该分子与钾通道相互作用，这对于调节信号疼痛涉及的神经元的活性很重要。我将使用这些抗体来确定LGI1的破坏是否是这些患者疼痛的原因，以及该蛋白是否是神经元活性的常见调节剂，因此是整个神经性疼痛的可行靶标。我的研究的目的是首先评估LGI1是否使用不再表达该蛋白质并评估其行为对感觉刺激的遗传改变的小鼠是否会影响疼痛感觉。使用这些小鼠，我将测量其疼痛信号神经元的活性，并通过其对钾通道的作用来确定LGI1是否影响该活动。通过我的合作，我将从许多神经性疼痛患者中获得LGI1自身抗体（-ABS）。我将使用这些样品开发动物模型，以确定这些抗体是否是神经性疼痛发展的因果。这项研究不仅会阐明LGI1在疼痛生物学中的作用，而且还将自身抗体作为引起患者疼痛异常的机制。我将使用已建立的神经损伤动物模型，以更好地了解LGI1在神经性疼痛发展中的作用。 LGI1是一个分泌的分子，其存在增加/稳定钾通道的活性（因此降低了疼痛信号神经元的活性）。为了测试调节该系统的治疗潜力，我将创建可溶性LGI1蛋白，以用于动物，以增加LGI1对疼痛信号神经元的可用性。使用临床前模型，我将测试LGI1治疗是否可以减少小鼠中的神经性疼痛行为，因此确定了这种方法的镇痛潜力。这些发现当然将直接帮助神经性疼痛患者患有LGI1-ABS，在该患者中已经可以使用治疗方法来降低抗体水平并可以专门治疗疼痛。在更广泛的背景下，神经性疼痛的新疗法将具有巨大的社会益处，这些发现可以应用于其他持续的疼痛状况。

项目成果

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

A role for pathogenic autoantibodies in small fiber neuropathy?

• DOI: 10.3389/fnmol.2023.1254854
• 发表时间: 2023
• 期刊: FRONTIERS IN MOLECULAR NEUROSCIENCE
• 影响因子: 4.8
• 作者: Daifallah, Omar;Farah, Adham;Dawes, John M.
• 通讯作者: Dawes, John M.

The structure of sensory afferent compartments in health and disease.

• DOI: 10.1111/joa.13544
• 发表时间: 2022-11
• 期刊: JOURNAL OF ANATOMY
• 影响因子: 2.4
• 作者: Middleton, Steven J.;Perez-Sanchez, Jimena;Dawes, John M.
• 通讯作者: Dawes, John M.

Corrigendum: A role for pathogenic autoantibodies in small fiber neuropathy?

• DOI: 10.3389/fnmol.2023.1336871
• 发表时间: 2023
• 期刊: FRONTIERS IN MOLECULAR NEUROSCIENCE
• 影响因子: 4.8
• 作者: Daifallah, Omar;Farah, Adham;Dawes, John M.
• 通讯作者: Dawes, John M.

A role for LGI1 in regulating pain sensitivity

• DOI: 10.1101/2023.09.13.557645
• 发表时间: 2023-09
• 期刊: bioRxiv
• 作者: Adham Farah;Ivan Paul;Hoi Cheng;Yuhe Su;Piotr Poplawski;Mandy Tseng;John M. Dawes