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: 10507771
• 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/10507771
• 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.

过去十年，我们结合分子遗传学、细胞生物学、离子通道等多学科研究 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 在疼痛中的作用 我们现在的目标是研究 NaV1.6 对化疗引起的疼痛和疼痛的影响。 周围神经病变 (CIPPN)，并确定 Nav1.6 的遗传变异是否会影响 对化疗药物介导的疼痛的敏感性这些研究将为疼痛的治疗选择提供信息。 以及基于药物基因组学的个性化策略，为癌症患者制定化疗处方。 化疗常常与钠离子通道病和神经病的发生有关。 此外，涉及 CIPPN 中 NaV1.6 的研究显示 DRG 中持续电流和复苏电流增强 我们实验室最近的工作发现了化疗药物奥沙利铂治疗后的神经元。 表明 Nav1.6 参与另一种化疗药物长春新碱引起的疼痛。 长春新碱引起的疼痛 (VIP) 的病理生理学和药理学，包括潜在的遗传风险 我们在本提案中的目标是调查 Nav1.6——一个重要的行动渠道。 有髓纤维中的潜在传播——在 CIPPN 中： a) 确定 Nav1.6 在 VIP 中的作用 b) 告知 基于药物基因组学的化疗以避免 CIPPN 的发展；以及 c) 开发一种新型非阿片类药物 基于 Nav1.6 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 的敲除研究表明该通道对 VIP 有贡献。 补偿机制可能会混淆观察到的结果，在这里，我们将敲除成年小鼠中的 Nav1.6。 评估以下指标，可以更好地为未来成人受试者的转化研究提供信息。 具体目标 2：评估 Nav1.6 的遗传变异是否为 VIP 的危险因素。 化疗导致 CI​​PPN，这表明遗传变异可能是对化疗过度反应的基础 我们的实验室首先证明了 Nav1.6 的功能获得 (GOF) 变异可导致化疗。 癫痫，一种类似于神经性疼痛的疾病，反映了潜在的神经元过度兴奋。 最近还在一名三叉神经痛患者的 NaV1.6 (Met136Val) 中发现了 GOF 变异， 这表明该变异可能使携带者容易患上疾病。 通道增加瞬态和恢复电流的幅度并增加神经放电。 我们的目标是在小鼠模型中检查 NaV1.6-M136V 是否会恶化 VIP。 具体目标 3：评估大麻素改善 VIP 的用途 大麻二酚 (CBD) 已获得 FDA 批准。 用于治疗某些形式的癫痫，并已被证明可以以一定的速度阻断复活的 NaV1.6 电流 浓度，以节省峰值瞬态电流，并降低神经兴奋性。 将确定 CBD 治疗是否可以改善 VIP 我们还将比较 CBD 与 VIP 的效果。 FDA 批准的度洛西汀 (Cymbalta®)，具有钠通道阻断活性，并已被证明 对治疗CIPPN有效。