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: 10293536
• 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/10293536
• 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 - Cell Movement; 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; 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，并且仍然是未满足的医疗需求。电压门控钠 在主要传入中更优选地表达的频道（NAV）在人类痛苦中起着至关重要的作用 疾病和目前的机会目标是开发新的疼痛治疗，这些疼痛治疗最少的中枢神经系统 副作用和添加潜力。 NAV1.7是一个调节动作电位的外围阈值通道 发射和神经递质释放。过去15年来，我们的工作将NAV1.7与人类疼痛障碍联系起来， 例如，遗传性红细胞，小纤维神经病，疼痛的糖尿病神经病和经过验证的NAV 1.7作为一个 高度吸引人的疼痛治疗目标。尽管在 开发新颖的NAV1.7阻滞剂以治疗疼痛，需要做很多工作以改善其 特异性和有效性。同样，尽管现有的NAV阻滞剂可以为患者提供症状缓解，但他们的 由于非特异性和明显的CNS副作用，实用性受到限制。 gabapentinoids是当前用于慢性疼痛的第一线治疗 钙通道的质膜或破坏Rab11依赖性回收，从而减少钙 电流和发射器释放。类似于gabapentinoids的疼痛治疗方式， 最近将关注贩运蛋白作为中枢神经系统疾病的治疗靶标，针对贩运机制 NAV1.7可能代表了一种新颖的疼痛治​​疗方法。但是，关于分子和 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的目标。 在此提案中，我们旨在阐明控制NAV1.7及其其运输的分子机制 在感觉神经元的轴突质膜中的分布，以确定潜在的新目标 慢性疼痛的治疗。具体来说，我们将建立一个我们开发的功能强大的新平台，该平台 在距SOMA距离的距离内实现活体感觉神经元内的单个钠通道的实时成像 具有前所未有的空间和临时分辨率。 从这些研究中清除的知识将为调节子的机制提供前所未有的清晰度 感觉神经元中钠通道的细胞分布，尤其是轴突的长度，正常 和疾病状态。反过来，这些研究将能够发现用于治疗慢性疼痛的新靶标。 我们的最终目标是开发更安全，更有效的治疗方法，而没有添加剂潜力和其他 严重的副作用。