Sodium Channel Nav1.6 in Chemotherapy-Induced Pain

钠通道 Nav1.6 在化疗引起的疼痛中的作用

• 批准号: 10311616
• 负责人: Sulayman D Dib-Hajj
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10311616
• 关键词: Action Potentials; Adult; Afferent Neurons; Axon; Behavioral; Biophysics; Cancer Patient; Cannabidiol; Cannabinoids; Cellular biology; Chronic; Clinical; Clinical Research; Cutaneous; Data; Development; Disease; Dose; Dropout; Embryo; Epidiolex; Epilepsy; Esthesia; FDA approved; Fiber; Functional disorder; Future; Genetic Variation; Goals; Healthcare Systems; Ion Channel; Knock-out; Laboratories; Malignant Neoplasms; Measures; Mediating; Medical; Molecular Genetics; Motor; Mus; Musculoskeletal Pain; Nerve Fibers; Neural Conduction; Neurons; Neuropathy; Numbness; Outcome; Pain; Pain Threshold; Patients; Peripheral Nervous System Diseases; Personal Satisfaction; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Physiology; Predisposition; Prevention; Property; Records; Research Design; Research Methodology; Risk Factors; Role; Sodium; Sodium Channel; Temperature; Testing; Trigeminal Neuralgia; Variant; Vincristine; Work; base; chemotherapeutic agent; chemotherapy; chronic pain; debilitating pain; density; diabetic; duloxetine; effective therapy; gain of function; genetic risk factor; genetic variant; in vivo; mouse model; multidisciplinary; neoplasm registry; neuronal excitability; neurotransmission; non-opioid analgesic; novel; oxaliplatin; pain sensitivity; painful neuropathy; response; sciatic nerve; spontaneous pain; translational study; treatment strategy

Over the past decade, our multi-disciplinary studies combining molecular genetics, cell biology, ion channel biophysics, sensory neuron physiology, and behavioral analysis have pinpointed the role of sodium channel NaV1.6 in pain. Our goal now is to investigate the contribution of NaV1.6 to chemotherapy-induced pain and peripheral neuropathy (CIPPN), and to determine whether genetic variants of Nav1.6 can influence susceptibility to pain mediated by chemotherapeutic drugs. These studies will inform treatment options for pain and personalized, pharmacogenomics-based strategies in prescribing chemotherapy to cancer patients. Chemotherapy is frequently associated with sodium channelopathy and the development of neuropathy. Furthermore, studies implicating NaV1.6 in CIPPN show enhanced persistent and resurgent currents in DRG neurons following treatment with the chemotherapeutic agent oxaliplatin. Recent work from our lab has suggested involvement of Nav1.6 in pain induced by vincristine, another chemotherapeutic agent. However, the pathophysiology and pharmacology of vincristine-induced pain (VIP) including underlying genetic risk factors remain unclear. Our goal in this proposal is to investigate Nav1.6—an essential channel for action potential propagation in myelinated fibers—in CIPPN to: a) Establish the role of Nav1.6 in VIP; b) Inform pharmacogenomics-based chemotherapy to avert development of CIPPN; and c) Develop a novel non-opioid based treatment strategy that targets Nav1.6 We will apply the following research design and methods to achieve our goal. Specific Aim 1: Assess the contribution of Nav1.6 to VIP in vivo. Our preliminary data from embryonic knockout studies of Nav1.6 suggests a contribution by this channel to VIP. However, it is possible that compensatory mechanisms may confound observed outcomes. Here, we will knockout Nav1.6 in adult mice to assess the following metrics that can better inform future translational studies in adult subjects. Specific Aim 2: Assess genetic variations in Nav1.6 as a risk factor for VIP. Not all patients who undergo chemotherapy develop CIPPN, which suggests that genetic variations may underlie exaggerated response to chemotherapy. Our laboratory was the first to show that gain-of-function (GOF) variants of Nav1.6 can cause epilepsy, a disorder similar to neuropathic pain that reflects underlying neuronal hyperexcitability. We have also recently identified a GOF variant in NaV1.6 (Met136Val) in a patient with painful trigeminal neuralgia, which suggests that this variant may predispose the carrier to the development of disease. NaV1.6-M136V channels increase amplitude of transient and resurgent currents and increase neuronal firing. In this specific aim we will examine whether NaV1.6-M136V exacerbates VIP in a mouse model. Specific Aim 3: Assess the use of cannabinoids to ameliorate VIP. Cannabidiol (CBD) is FDA-approved for treatment of some forms of epilepsy and has been shown to block resurgent NaV1.6 currents at a concentration that spares peak transient current, and to reduce neuronal excitability. In this specific aim, we will determine whether treatment with CBD can ameliorate VIP. We will also compare the effect of CBD to FDA-approved duloxetine (Cymbalta®), which has sodium channel blocking activity and has been shown to be effective for treatment of CIPPN.

在过去的十年中，我们的多学科研究结合了分子遗传学，细胞生物学，离子通道 生物物理学，感觉神经元生理学和行为分析已经确定了钠通道的作用 NAV1.6疼痛。我们现在的目标是研究NAV1.6对化学疗法诱导的疼痛和 周围神经病（CIPPN），并确定NAV1.6的遗传变异是否会影响 化学治疗药物介导的疼痛的敏感性。这些研究将为治疗方案提供痛苦的选择 以及个性化的，基于药物基础学的策略，用于为癌症患者开化化疗。 化学疗法经常与通道病钠和神经病的发展有关。 此外，在CIPPN中暗示NAV1.6的研究显示DRG中的持久性和复兴电流增强 用化学治疗剂奥沙利铂治疗后的神经元。我们实验室的最近工作 提示NAV1.6参与另一种化学治疗剂Vincristine引起的疼痛。然而， 长春新碱诱导的疼痛（VIP）的病理生理学和药理学，包括潜在的遗传风险 因素仍然不清楚。我们在此提案中的目标是调查NAV1.6 - 行动的重要渠道 髓鞘纤维中的潜在繁殖 - 在CIPPN至：a）确定NAV1.6在VIP中的作用； b）告知 基于药物基因组学的化学疗法避免了CIPPN的发展； c）发展一种新颖的非阿片类药物 针对NAV1.6的基于基于的治疗策略 我们将应用以下研究设计和方法来实现我们的目标。 具体目标1：评估NAV1.6对体内VIP的贡献。我们来自胚胎的初步数据 NAV1.6的敲除研究表明该渠道对VIP做出了贡献。但是，有可能 补偿机制可能会混淆观察到的结果。在这里，我们将在成年小鼠中淘汰NAV1.6 评估以下指标，可以更好地为成人受试者提供未来的翻译研究。 特定目标2：评估NAV1.6中的遗传变异是VIP的危险因素。并非所有经历的患者 化学疗法发展了CIPPN，这表明遗传变异可能是对 化学疗法。我们的实验室是第一个表明NAV1.6的功能障碍（GOF）变体可能引起的。 癫痫病是一种类似于神经性疼痛的疾病，反映了基本的神经性过度兴奋性。我们有 最近还确定了疼痛三叉神经痛患者的NAV1.6（MET136VAL）中的GOF变体， 这表明这种变体可能使携带者易于疾病的发展。 NAV1.6-M136V 通道会增加瞬时和复活电流的振幅，并增加神经元的发射。在这个特定的情况下 目的，我们将检查鼠标模型中的NAV1.6-M136V是否加剧了VIP。 特定目标3：评估大麻素的使用来改善VIP。大麻二酚（CBD）是FDA批准的 为了治疗某些形式的癫痫病，已被证明可以阻止复兴的NAV1.6电流 节省峰值瞬态电流并减少神经元令人兴奋的浓度。在这个具体目标中，我们 将确定用CBD处理是否可以改善VIP。我们还将将CBD的效果与 FDA批准的Duloxetine（Cymbalta®），具有钠通道阻塞活性，已被证明为 有效治疗CIPPN。