Contribution of Local Translation to Nerve Injury-Induced Upregulation of Nav1.1 in Trigeminal Nerves

局部翻译对神经损伤引起的三叉神经 Nav1.1 上调的贡献

• 批准号: 10382015
• 负责人: Jeremy Gedeon
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382015
• 关键词: Accounting; Action Potentials; Acute; Address; Affect; Afferent Neurons; Anatomy; Anisomycin; Attenuated; Axon; Behavior; Behavioral; Biochemical; Cells; Colchicine; Consensus; Data; Electrophysiology (science); Ensure; Face; Future; Genetic Translation; Goals; Hypersensitivity; Image; Immunohistochemistry; Injury; Lead; Ligation; Literature; Mechanics; Messenger RNA; Microtubules; Modeling; Nerve; Neurons; Neurosciences; Nociception; Pain; Peripheral; Peripheral Nerves; Peripheral nerve injury; Persistent pain; Persons; Pharmacology; Prevalence; Protein Synthesis Inhibitors; Proteins; Research Personnel; SCN1A protein; Science; Series; Site; Sodium Channel; Stimulus; Structure of trigeminal ganglion; Techniques; Testing; Therapeutic; Therapeutic Intervention; Training; Translations; Trigeminal System; Trigeminal nerve structure; Universities; Up-Regulation; Western Blotting; Work; career; chronic constriction injury; chronic pain; collaborative environment; comparative; density; disability; experimental study; in vivo; inhibitor; mechanical stimulus; nerve injury; new therapeutic target; novel therapeutic intervention; pain behavior; painful neuropathy; preference; prevent; protein transport; response; response to injury; success; therapeutic target; therapeutically effective; trafficking; voltage

PROJECT SUMMARY/ABSTRACT Chronic pain is both highly prevalent and a major cause of disability, affecting approximately 20.4% of the U.S. Despite this prevalence, there are still limited therapeutic options. These issues are particularly true for pain associated with trigeminal nerve injury. Recent comparative analyses support the presence of differences between trigeminal and somatic nerves regarding the response to injury, and also point to voltage-gated sodium channels (VGSCs) as a potential mechanism accounting for both the pain and differences in the efficacy of available therapeutic interventions. Furthermore, VGSCs accumulation at the site of nerve injury and changes in the relative density of subtypes in sensory neuron cell bodies have been implicated in the ongoing pain and hypersensitivity associated with peripheral nerve injury. There is no consensus in the literature as to which of the VGSC subtype(s) underlie action potential (AP) propagation along peripheral nerves, or which subtypes underlie AP propagation following injury. However, there is evidence that the redistribution of VGSC subunits along peripheral axons enables the nerve injury-induced pain and hypersensitivity, and therefore may serve as a viable therapeutic target. In this regard, we have preliminary data suggesting that trigeminal but not the somatic nerve injury is associated with an increase in functional NaV1.1 channels in trigeminal nerve axons that when blocked, reverse nerve injury-induced mechanical sensitivity. Two general mechanisms have been implicated in changes in axonal VGSC channels: protein trafficking and local translation of mRNA. While both mechanisms are possible, at least two lines of evidence suggest local translation may underly the nerve injury-induced increase in NaV1.1 in trigeminal axons. Thus, I hypothesize that the change in distribution of NaV1,1 in trigeminal nerves following injury is due to local translation, and that the increase in functional NaV1.1 axonal protein contributes to injury-induced hypersensitivity. To test this hypothesis, I will use a combination of techniques that will elucidate the contribution of local translation and protein trafficking to nerve-injury induced hypersensitivity in a series of experiments described under three specific aims involving anatomical and biochemical techniques (Aim 1), functional endpoints (Aim 2), and behavioral endpoints (Aim 3). Results from these aims will determine the basis for the nerve injury-induced increase in NaV1.1 in trigeminal nerve axons and their contribution to changes in nociception. Future studies will address the implications for these results for novel therapeutic approaches to the treatment of neuropathic pain. Along with the state-of-the-art facilities available, the highly collaborative environment in the Center for Neuroscience at the University of Pittsburgh will ensure the successful completion of the experiments proposed. These studies will also provide me with the technical and intellectual training required to become an independent investigator in the field of pain, while the commitment to diversity in the CNUP will allow me to pursue my career goal of promoting inclusion in science.

项目摘要/摘要 慢性疼痛既普遍又是残疾的主要原因，影响了美国约20.4％ 尽管存在这种流行，但治疗选择仍然有限。这些问题特别适合痛苦 与三叉神经损伤有关。最近的比较分析支持差异的存在 在三叉神经和躯体神经之间关于损伤的反应，也指向电压门控钠 渠道（VGSC）是一种潜在的机制，涉及疼痛和差异 可用的治疗干预措施。此外，VGSC在神经损伤部位积累并改变 在感觉神经元细胞中亚型的相对密度中，已经与正在进行的疼痛和 与周围神经损伤有关的超敏反应。关于哪个的文献尚无共识 VGSC亚型（S）沿周围神经的动作电位（AP）繁殖的基础，或哪个亚型 受伤后AP传播的基础。但是，有证据表明VGSC亚基的重新分布 沿着外围轴突可实现神经损伤引起的疼痛和超敏反应，因此可以用作 一个可行的治疗靶标。在这方面，我们有初步数据表明三叉神经，但不是躯体 神经损伤与三叉神经轴突中功能性NAV1.1通道的增加有关 阻塞，反向神经损伤引起的机械灵敏度。两种一般机制与 轴突VGSC通道的变化：蛋白质运输和mRNA的局部翻译。而这两种机制 至少有两条证据表明局部翻译可能是神经损伤引起的 三叉子轴突中NAV1.1的增加。因此，我假设三叉神经中NAV1,1的分布变化 受伤后的神经是由于局部翻译而引起的，功能性NAV1.1轴突蛋白的增加 导致损伤引起的超敏反应。为了检验这一假设，我将使用多种技术的组合 将阐明局部翻译和蛋白质运输对神经伤害的贡献 在涉及解剖学和生化技术的三个特定目的下描述的一系列实验中 （AIM 1），功能终点（AIM 2）和行为端点（AIM 3）。这些目标的结果将决定 神经损伤引起的三叉神经轴突中NAV1.1增加的基础及其对 伤害感受。未来的研究将解决这些结果对新型治疗的影响 治疗神经性疼痛的方法。以及最先进的设施，高度 匹兹堡大学神经科学中心的协作环境将确保 提出的实验成功完成。这些研究还将为我提供技术和 成为痛苦领域的独立调查员需要的知识培训，而对 CNUP中的多样性将使我能够追求促进科学中的职业目标。