Regulation of M-type K+ channel expression in sensory neurones as a novel mechanism contributing to chronic pain states

感觉神经元中 M 型 K 通道表达的调节作为导致慢性疼痛状态的新机制

• 批准号: G1002183/1
• 负责人: Nikita Gamper
• 金额: $ 66.48万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1002183%2F1
• 关键词: Regulation; type; K+; channel; expression

Chronic pain constitutes an enormous health problem. It brings physical and psychological distress to the sufferers and their carers and puts significant pressure on the health care system. It is especially true because many types of chronic pains are particularly difficult to treat, most of the conventional analgesics are either ineffective or have serious side-effects. One of the common primary causes of many chronic pain conditions is an uncontrolled activity of specific peripheral nerves which normally are silent and only become active in response to potentially damaging stimulation. This pathological activity of damage-sensing nerves (peripheral sensitisation) may last for months or years (e.g. in arthritis or neuropathic pain) causing unrestrained pain. Unfortunately, despite of much effort, the mechanisms underlying peripheral sensitisation are poorly understood. Recent work in the laboratories of the applicants has lead up to the accumulation of a ?critical mass? of evidence towards the discovery of what may become one of the key molecular mechanism contributing to the chronic pain. Our findings revealed that nerve injury triggers long-lasing down-regulation of specific group of genes that encode family of proteins called ?M-type potassium channels? that control activity of peripheral nerves. Importantly, we identified another protein called ?REST?, which is able to specifically interact with and regulate expression of the M-type potassium channel genes. Our hypothesis (supported by our recently published and yet unpublished data) is that nerve injury or inflammation triggers the expression of REST which, in turn, suppresses the expression of M-type potassium channels in peripheral sensory nerves thus increasing their spontaneous activity. The aim of this proposal is to perform comprehensive and rigorous investigation of this novel mechanism. We will use known animal models for neuropathic pain in combination with an array of cutting edge genetic, molecular, biochemical and electrophysiological approaches to fully characterise the changes in the expression patterns of the M-type potassium channel genes induced by nerve injury. We will further probe the mechanism responsible for control of M-channel expression and function in sensory nerves with particular attention to the newly discovered role of REST. Our work has the potential to identify new targets and strategies that may be used to develop better medicines for the treatment and management of chronic pain.

慢性疼痛构成了一个巨大的健康问题。它给患者及其护理人员带来身心困扰，并给医疗保健系统带来巨大压力。尤其如此，因为许多类型的慢性疼痛特别难以治疗，大多数常规镇痛药要么无效，要么有严重的副作用。许多慢性疼痛的常见主要原因之一是特定周围神经的不受控制的活动，这些神经通常是沉默的，只有在响应潜在的破坏性刺激时才变得活跃。损伤感知神经（外周敏化）的这种病理活动可能持续数月或数年（例如关节炎或神经性疼痛），导致无法抑制的疼痛。不幸的是，尽管付出了很多努力，但人们对外周敏化背后的机制知之甚少。申请人实验室最近的工作已经积累了“临界质量”。发现可能成为导致慢性疼痛的关键分子机制之一的证据。我们的研究结果表明，神经损伤会引发编码“M 型钾通道”蛋白质家族的特定基因组的长期下调。控制周围神经的活动。重要的是，我们发现了另一种名为“REST”的蛋白质，它能够特异性地与 M 型钾通道基因相互作用并调节其表达。我们的假设（得到我们最近发表且尚未发表的数据的支持）是，神经损伤或炎症触发 REST 的表达，而 REST 的表达反过来又抑制周围感觉神经中 M 型钾通道的表达，从而增加其自发活动。该提案的目的是对这种新颖的机制进行全面而严格的研究。我们将使用已知的神经性疼痛动物模型，结合一系列尖端的遗传、分子、生化和电生理学方法，以充分表征神经损伤引起的 M 型钾通道基因表达模式的变化。我们将进一步探讨控制感觉神经 M 通道表达和功能的机制，特别关注新发现的 REST 作用。我们的工作有可能确定新的目标和策略，可用于开发更好的药物来治疗和管理慢性疼痛。