Using FHF2 to Adjust the Gain on Pain

与平民相比，退伍军人慢性疼痛的患病率更高。当前的治疗方法 严重依赖阿片类药物的使用。缺乏适当的替代治疗导致在#年过度使用阿片类药物。 疼痛的管理。这些事实突显了对替代疼痛治疗选择的迫切需要。 这项提案中概述的工作将集中在电压门控钠通道Nav1.7，这是一个重要的组件 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痛症 (IEM)一种慢性疼痛综合征，表现为四肢远端由热引起的灼痛。其他 导致Nav1.7活性降低的同一通道中的突变导致先天性对疼痛不敏感 (CIP)患者感觉不到疼痛，即他们遭受无痛性骨折、烧伤和分娩。 由于在人类病例中的这种验证，NAV1.7已成为治疗糖尿病的一个有吸引力的靶点。 慢性疼痛。 拟议的研究将建立在最近发表的工作的基础上，这些工作证明了成纤维细胞生长因子同源 因子2(FHF2)与Nav1.7相互作用，并在天然背根神经节(DRG)中被敲除 神经元导致Nav1.7活性增加。这项工作将利用基因疗法来确定 过表达FHF2是否会导致Nav1.7活性丧失功能，从而减弱 神经损伤后伤害性感受器兴奋性(疼痛的代用品)。 这一建议旨在进一步阐明神经损伤与神经元过度兴奋性之间的联系机制。它 已有研究表明FHF2在神经轴突切断后表达下调。FHF2基因的敲除导致了- NAV1.7活性的功能变化，NA1.7已被认为与神经元的过度兴奋有关。我们将利用 一种RNA干扰方法以异构体依赖的方式敲除FHF2水平并测量 多电极阵列分析对神经元兴奋性的影响，以确定FHF2是一种 在将神经损伤与过度兴奋和疼痛联系起来的机制中的重要因素。我们将进一步 用电流钳电生理学研究观察到的兴奋性变化的机制。 对这一机制的深入了解可能会揭示出更多针对 FHF2诱导的Nav1.7调制是减轻神经损伤后神经病理性疼痛的一种途径。 这项研究计划的最终目标是找到治疗神经病理性慢性疼痛的替代方法。 起源。这项工作将应用于治疗创伤和烧伤相关的神经病理性疼痛，如果 成功，将对改善饱受痛苦折磨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.