Dynamic regulation of axonal trafficking and surface distribution of Nav1.7 in sensory neurons

感觉神经元轴突运输和 Nav1.7 表面分布的动态调节

• 批准号: 10618775
• 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: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618775
• 关键词: AGFG1 gene; Action Potentials; Afferent Neurons; Aftercare; Animal Model; Ankyrins; Applications Grants; Axon; Binding; Biogenesis; Calcium; Calcium Channel; Cell membrane; Central Nervous System Diseases; Cytoskeleton; Deposition; Development; Diabetes Mellitus; Diabetic Neuralgia; Disease; Distal; Erythromelalgia; Fiber; Glean; Goals; Human; Inflammation; Inflammation Mediators; Inherited; Kinesin; Knowledge; Label; Length; Link; Medical; Membrane; Methodology; Mitogen-Activated Protein Kinases; Molecular; Monomeric GTP-Binding Proteins; Motor; Multiple Trauma; Neurons; Neuropathy; Nociceptors; Opioid; Outcome; Pain; Pain Disorder; Pain management; Paper; Patients; Peripheral; Phosphorylation; Play; Proteins; Publications; Recycling; Regulation; Risk; Role; Sensory; Sodium Channel; Sorting; Specificity; Speed; Surface; Traumatic Nerve Injury; Traumatic Neuroma; Vesicle; Veterans; Work; addiction; channel blockers; chronic pain; chronic pain management; effective therapy; experimental study; gabapentin; improved; in vivo; inhibitor; knock-down; limb amputation; meter; nanocluster; neuronal cell body; neurotransmitter release; novel; novel strategies; pregabalin; presynaptic; protein transport; real-time images; side effect; temporal measurement; therapeutic target; trafficking; vesicle transport; voltage

Chronic pain is common among Veterans and remains an unmet medical need. Voltage-gated sodium channels (NaVs) that are expressed preferentially in primary afferents play a critical role in human pain disorders, and present opportune targets for the development of novel pain treatments that carry minimal CNS side effects and addictive potential. NaV1.7 is a peripheral threshold channel that regulates action potential firing and neurotransmitter release. Our work for the past 15 years has linked NaV1.7 to human pain disorders, e.g., inherited erythromelalgia, small fiber neuropathy, painful diabetic neuropathy, and validated NaV 1.7 as a highly attractive target for the treatment of pain. Although considerable progress has been made in the development of novel NaV1.7 blockers for the treatment of pain, much work is needed to improve their specificity and efficacy. Similarly, while existing NaV blockers can provide symptomatic relief in patients, their utility is limited due to non-specificity and significant CNS side effects. Gabapentinoids, the current first line treatment for chronic pain, inhibit trafficking of presynaptic voltage-gated calcium channel to the plasma membrane or disrupt Rab11-dependent recycling, thus reducing calcium currents and transmitter release. By analogy to gabapentinoids' mode of action for the treatment of pain, and recent focus on trafficking proteins as therapeutic targets in CNS disorder, targeting trafficking machinery of Nav1.7 might represent a novel approach to pain treatment. However, little is known about molecules and mechanisms that control sodium channel trafficking and surface distribution along the length of sensory axons—a target of opportunity that we explore in this proposal. In this proposal, we aim to elucidate molecular mechanisms that control trafficking of NaV1.7 and their distribution in the axonal plasma membrane of sensory neurons, in an effort to identify potential new targets for the treatment of chronic pain. Specifically, we will build upon a powerful new platform that we developed, that enables real-time imaging of single sodium channels within living sensory neurons at a distance from the soma with unprecedented spatial- and temporal-resolution. Knowledge gleaned from these studies will provide unprecedented clarity about mechanisms that regulate sub- cellular distribution of sodium channels in sensory neurons, particularly along the length of axons, in normal and disease states. These studies, in turn, will enable discovery of new targets for treatment of chronic pain. Our ultimate goal is to develop safer and more effective treatments without addictive potential and other serious side effects.

慢性疼痛在退伍军人中很常见，并且仍然是电压门控钠的未满足的医疗需求。 在初级传入神经中优先表达的通道（NaV）在人类疼痛中发挥着关键作用 疾病，并为开发携带最小中枢神经系统的新型疼痛治疗方法提供了合适的目标 副作用和成瘾潜力 NaV1.7 是调节动作电位的外周阈值通道。 我们过去 15 年的工作已将 NaV1.7 与人类疼痛疾病联系起来。 例如，遗传性红斑性肢痛症、小纤维神经病、疼痛性糖尿病神经病，并验证 NaV 1.7 作为 尽管在疼痛治疗方面已经取得了相当大的进展，但它是非常有吸引力的目标。 开发用于治疗疼痛的新型 NaV1.7 阻滞剂，需要做大量工作来改善其效果 同样，虽然现有的 NaV 阻滞剂可以缓解患者的症状，但它们的效果却不尽如人意。 由于非特异性和显着的中枢神经系统副作用，实用性受到限制。 加巴喷丁类药物是目前治疗慢性疼痛的一线药物，可抑制突触前电压门控信号的运输 钙通道通向质膜或破坏 Rab11 依赖性循环，从而减少钙 类似于加巴喷丁治疗疼痛的作用方式，以及 最近的重点是贩​​运蛋白质作为中枢神经系统疾病的治疗靶点，针对贩运机制 Nav1.7 可能代表了一种新的疼痛治疗方法，然而，人们对分子和机制知之甚少。 控制钠通道运输和沿感觉长度的表面分布的机制 轴突——我们在本提案中探索的机会目标。 在本提案中，我们的目标是阐明控制 NaV1.7 及其运输的分子机制 感觉神经元轴突质膜中的分布，以努力确定潜在的新靶点 具体来说，我们将建立在我们开发的一个强大的新平台之上。 能够对距体体一定距离的活感觉神经元内的单个钠通道进行实时成像 具有前所未有的空间和时间分辨率。 从这些研究中收集的知识将为调节亚健康的机制提供前所未有的清晰度。 正常情况下，感觉神经元中钠通道的细胞分布，特别是沿着轴突的长度 反过来，这些研究将有助于发现治疗慢性疼痛的新靶点。 我们的最终目标是开发更安全、更有效的治疗方法，且不会产生成瘾性和其他副作用 严重的副作用。