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

神经系统的创伤或糖尿病等疾病可能会损伤与疼痛信号有关的神经元，导致它们变得过度活跃，并引发不适的痛感。这种类型的疼痛称为神经病理性疼痛，令人不快，持续时间长，并导致患者的生活质量下降。神经性疼痛是一种常见的疼痛，影响着5%-10%的人，随着人口老龄化，这种疼痛将变得更加常见。虽然有镇痛剂可用，但这种类型的疼痛对我们目前的治疗策略特别有抵抗力，让患者几乎没有选择。此外，这些药物还会产生严重的副作用。当然，这对个人来说是极大的削弱，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、下班时间)，总体上是医疗服务的负担，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病理性疼痛。其中一个障碍是缺乏从基础科学成果到临床的转化。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失活1(LGI1)的自身抗体与患者的神经病理性疼痛有关。这种分子与钾通道相互作用，钾通道对调节参与传递疼痛信号的神经元的活动非常重要。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，以及这种蛋白是否是神经元活动的常见调节因素，从而成为治疗神经病理性疼痛的可行靶点。我的研究目的将首先通过使用不再表达LGI1蛋白的转基因小鼠来评估LGI1是否对痛觉产生影响，并评估它们对感觉刺激的行为。利用这些小鼠，我将测量它们疼痛信号神经元的活动，并确定LGI1是否通过对钾通道的作用影响这一活动。通过我的合作，我将从许多神经病理性疼痛患者那里获得LGI1自身抗体(-Abs)。我将利用这些样本建立一个动物模型，以确定这些抗体是否与神经病理性疼痛的发生有关。这项研究不仅将阐明LGI1在疼痛生物学中的作用，还将阐明自身抗体作为引起患者异常痛感的机制。我将使用已建立的神经损伤动物模型来更好地了解LGI1在神经病理性疼痛发展中的作用。LGI1是一种分泌分子，它的存在增加/稳定了钾通道的活性(从而降低了痛信号神经元的活性)。为了测试调节这一系统的治疗潜力，我将创造用于动物的可溶性LGI1蛋白，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的神经病理性疼痛行为，从而确定这种方法的止痛潜力。这些发现当然将直接帮助使用LGI1-Abs的神经病理性疼痛患者，这些治疗方法已经可以降低抗体水平，然后可以专门用于治疗疼痛。在更广泛的背景下，神经病理性疼痛的新治疗方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。

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.