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伤参与疼痛信号传递的神经元，导致它们变得过度活跃并引发令人不快的疼痛感。这种类型的疼痛，称为神经性疼痛，是不愉快的，持久的，并导致患者的生活质量差。神经性疼痛通常影响5-10%的人，并且随着人口老龄化将变得更加常见。虽然有止痛药，但这种类型的疼痛对我们目前的治疗策略特别有抵抗力，使患者几乎没有选择。此外，这些药物会引起严重的副作用。这当然会极大地削弱个人，对他们的生活方式产生负面影响。此外，它具有重大的经济后果（治疗费用，下班时间），并且通常是医疗保健服务的负担，需要加以解决。因此，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临床的转化。在这里，我的目标是通过使用患者样本来提高我的研究结果的临床相关性来解决这个问题。针对富含亮氨酸的胶质瘤GLI 1（LGI 1）的自身抗体与患者的神经病理性疼痛相关。这种分子与钾通道相互作用，钾通道对于调节参与疼痛信号传导的神经元的活性很重要。我将使用这些抗体来确定LGI 1的破坏是否是这些患者疼痛的原因，以及这种蛋白质是否是神经元活动的常见调节因子，因此是否是治疗神经性疼痛的可行靶点。我研究的目的是首先评估LGI 1是否会影响痛觉，方法是使用基因改变的小鼠，这些小鼠不再表达这种蛋白质，并评估它们对感官刺激的行为。使用这些小鼠，我将测量它们的疼痛信号神经元的活动，并确定LGI 1是否通过其对钾通道的作用影响这种活动。通过我的合作，我将从一些神经性疼痛患者中获得LGI 1自身抗体（Abs）。我将使用这些样本来建立动物模型，以确定这些抗体是否是神经性疼痛发生的原因。这项研究不仅将阐明LGI 1在疼痛生物学中的作用，还将阐明自身抗体作为导致患者异常疼痛感觉的机制。我将使用已建立的神经损伤动物模型，以更好地了解LGI 1在神经性疼痛发展中的作用。LGI 1是一种分泌性分子，其存在增加/稳定钾通道的活性（因此降低疼痛信号神经元的活性）。为了测试调节该系统的治疗潜力，我将创造可溶性LGI 1蛋白用于动物，以增加LGI 1对疼痛信号神经元的可用性。使用临床前模型，我将测试LGI 1治疗是否可以减少小鼠的神经性疼痛行为，从而确定这种方法的镇痛潜力。这些发现当然将直接帮助患有LGI 1抗体的神经性疼痛患者，其中已经有治疗方法可以降低抗体水平，然后可以专门用于治疗疼痛。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效益，这些发现可以应用于其他持续性疼痛状况。

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.

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

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.