Using FHF2 to Adjust the Gain on Pain

与平民相比，退伍军人的慢性疼痛患病率更高。当前治疗 严重依赖阿片类药物缺乏足够的替代治疗导致阿片类药物过度使用， 疼痛的管理。这些事实突出了对替代疼痛治疗选择的迫切需要。 在这项提案中概述的工作将集中在电压门控钠通道Nav1.7，一个重要的组成部分， 在人类疼痛信号中。Nav1.7中的单个氨基酸突变导致人类至少两种已知疾病 与疼痛有关。导致通道活性增加的突变会导致遗传性红斑性肢痛症 (IEM)一种慢性疼痛综合征，表现为热引起的末端灼热疼痛。其他 导致Nav1.7活性降低的同一通道中的突变导致先天性疼痛不敏感 (CIP)其中患者不会感到疼痛，即，她们遭受无痛骨折、烧伤和分娩的痛苦。 由于在人类病例中的这种验证，Nav1.7已经成为治疗糖尿病的有吸引力的靶标。 慢性疼痛 拟议的研究将建立在最近发表的工作，这表明FGF同源 因子2（FHF 2）与Nav1.7相互作用，并且在天然背根神经节（DRG）中敲低FHF 2 神经元导致Nav1.7活性增加。这项工作将利用基因治疗方法来确定 FHF 2的过表达是否可以赋予Nav1.7活性的功能丧失属性，从而减弱 神经损伤后的伤害感受器兴奋性（疼痛的代理）。 该建议旨在进一步阐明神经损伤与神经元过度兴奋的机制。它 已经显示，FHF 2在神经轴突切断后下调。FHF 2的敲除导致 Nav1.7活性的功能变化，Nav1.7与神经元过度兴奋有关。我们将利用 RNA干扰方法以同种型依赖性方式敲低FHF 2水平，并测量FHF 2水平。 使用多电极阵列分析对神经元兴奋性的影响，以确定FHF 2是一种 是神经损伤与兴奋过度和疼痛联系机制中的一个重要因素。我们将进一步 使用电流钳电生理学研究观察到的兴奋性变化的机制。 对这一机制的更深入理解可能会揭示更多的机会， FHF 2诱导Nav1.7调节作为减轻神经损伤后神经病理性疼痛的方式。 这项研究计划的最终目标是发现一种替代方法来治疗慢性疼痛的神经病变 起源这项工作将应用于治疗创伤和烧伤相关的神经性疼痛，如果 成功后，将对改善患有疼痛的退伍军人的生活质量产生重要影响。

The prevalence of chronic pain is higher in Veterans compared to the civilian population. Current treatments rely heavily on the use of opioids. The lack of adequate alternative treatments has led to overuse of opioids in the management of pain. These facts highlight the urgent need for alternative pain treatment options. The work outlined in this proposal will focus on voltage-gated sodium channel Nav1.7, an important component in human pain signaling. Single amino acid mutations in Nav1.7 cause at least two known diseases in humans related to pain. Mutations that lead to an increase in activity in the channel cause inherited erythromelalgia (IEM) a chronic pain syndrome that manifests as heat-induced burning pain in the distal extremities. Other mutations in the same channel that lead to decreased activity in Nav1.7 cause congenital insensitivity to pain (CIP) in which patients do not feel pain, i.e., they suffer from painless bone fractures, burns and childbirth. Because of this validation in human cases, Nav 1.7 has emerged as an attractive target in the treatment of chronic pain. The proposed research will build upon recently published work, which demonstrated that FGF homologous factor 2 (FHF2) interacts with Nav1.7, and that knockdown of FHF2 in native dorsal root ganglion (DRG) neurons results in increased Nav1.7 activity. This work will utilize a gene therapy approach to determine whether overexpression of FHF2 can confer loss-of-function attributes to Nav1.7 activity and thereby attenuate nociceptor excitability (a proxy for pain) after nerve injury. This proposal aims to further elucidate the mechanisms linking nerve damage to neuronal hyperexcitability. It has been shown that FHF2 is downregulated after nerve axotomy. Knockdown of FHF2 leads to gain-of- function changes in Nav1.7 activity, and Nav1.7 has been linked to neuronal hyperexcitability. We will utilize an RNA interference approach to knockdown FHF2 levels in an isoform dependent manner and measure the effects on neuronal excitability using multielectrode array analysis, in order to determine that FHF2 is an important factor in a mechanism that links nerve damage to hyperexcitability and pain. We will further investigate the mechanism underlying observed changes in excitability using current clamp electrophysiology. A deeper understanding of this mechanism might reveal additional opportunities to target the mechanism of FHF2 induced Nav1.7 modulation as a way of attenuating neuropathic pain after nerve injury. The ultimate goal of this research program is to discover an alternative way to treat chronic pain of neuropathic origin. This work will have applications for treating both trauma and burn related neuropathic pain, and if successful, will have an important impact on improving the quality of life of Veterans afflicted with pain.