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: 10540723
• 负责人: Jeremy Gedeon
• 金额: $ 4.77万
• 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/10540723
• 关键词: Accounting; Action Potentials; Acute; Address; Affect; Afferent Neurons; Anatomy; Anisomycin; Attenuated; Axon; Behavior; Behavioral; Biochemical; Colchicine; Consensus; Data; Electrophysiology (science); Ensure; Face; Future; Goals; Hypersensitivity; Image; Immunohistochemistry; Injury; Ligation; Literature; Mechanics; Messenger RNA; Microtubules; Modeling; Nerve; Neurons; Neurosciences; Nociception; Pain; Peripheral; Peripheral Nerves; Peripheral nerve injury; Persistent pain; Persons; 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; Visualization; Western Blotting; Work; antinociception; career; chronic constriction injury; chronic pain; collaborative environment; comparative; density; disability; experimental study; in vivo; inhibitor; mRNA Translation; mechanical stimulus; nerve injury; neuronal cell body; new therapeutic target; novel therapeutic intervention; pain behavior; painful neuropathy; pharmacologic; 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.

项目概要/摘要 慢性疼痛非常普遍，也是导致残疾的主要原因，影响了大约 20.4% 的美国人口。 尽管这种情况很普遍，但治疗选择仍然有限。这些问题对于疼痛尤其如此 与三叉神经损伤有关。最近的比较分析支持差异的存在 三叉神经和躯体神经之间关于对损伤的反应，也指向电压门控钠 通道（VGSC）作为一种潜在机制，可以解释疼痛和功效差异 可用的治疗干预措施。此外，VGSCs 在神经损伤部位的积累和变化 感觉神经元细胞体亚型的相对密度与持续的疼痛和 与周围神经损伤相关的超敏反应。文献中对于哪一个没有达成共识 VGSC 亚型是动作电位 (AP) 沿周围神经传播的基础，或者哪些亚型 是损伤后 AP 传播的基础。然而，有证据表明 VGSC 亚基的重新分配 沿着周围轴突可以缓解神经损伤引起的疼痛和过敏，因此可以作为 一个可行的治疗目标。在这方面，我们有初步数据表明，三叉神经而不是躯体 神经损伤与三叉神经轴突中功能性 NaV1.1 通道的增加有关，当 阻断、逆转神经损伤引起的机械敏感性。涉及两种一般机制 轴突 VGSC 通道的变化：蛋白质运输和 mRNA 的局部翻译。虽然这两种机制 是可能的，至少有两条证据表明局部翻译可能是神经损伤引起的原因 三叉神经轴突中 NaV1.1 增加。因此，我假设三叉神经中 NaV1,1 分布的变化 损伤后的神经是由于局部翻译，以及功能性 NaV1.1 轴突蛋白的增加 有助于损伤引起的超敏反应。为了检验这个假设，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损伤引起的超敏反应的贡献 在涉及解剖和生化技术的三个具体目标下描述的一系列实验中 （目标 1）、功能终点（目标 2）和行为终点（目标 3）。这些目标的结果将决定 神经损伤引起的三叉神经轴突 NaV1.1 增加的基础及其对 伤害感受的变化。未来的研究将解决这些结果对新疗法的影响 治疗神经性疼痛的方法。除了最先进的设施外，高度 匹兹堡大学神经科学中心的协作环境将确保 成功完成所提出的实验。这些研究还将为我提供技术和 成为疼痛领域的独立研究者所需的智力培训，同时致力于 CNUP 的多样性将使我能够追求促进科学包容性的职业目标。