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

项目总结/摘要 慢性疼痛是非常普遍的，也是残疾的主要原因，影响了大约20.4%的美国人。 尽管这种流行，仍然有有限的治疗选择。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存在差异 三叉神经和躯体神经对损伤的反应之间的关系，也指向电压门控钠 通道（VGSC）作为一种潜在的机制，既解释了疼痛，也解释了 可用的治疗干预措施。此外，VGSCs在神经损伤部位的积聚和变化 感觉神经元细胞体中亚型的相对密度与持续的疼痛有关， 与周围神经损伤相关超敏反应。在文献中没有达成共识， VGSC亚型是动作电位（AP）沿周围神经沿着传播基础，或者哪些亚型 是损伤后AP传播的基础。然而，有证据表明，VGSC亚基的重新分布 沿着外周轴突使神经损伤引起的疼痛和超敏反应，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 神经损伤与三叉神经轴突中功能性NaV1.1通道的增加有关， 阻断，逆转神经损伤引起的机械敏感性。有两种一般机制涉及到 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 至少有两条证据表明，局部翻译可能是神经损伤引起的 三叉神经轴突中的NaV1.1增加。因此，我假设三叉神经中NaV 1，1分布的变化 损伤后的神经是由于局部翻译，功能性NaV1.1轴突蛋白的增加， 导致损伤引起的超敏反应。为了验证这个假设，我将使用一组技术， 将阐明局部翻译和蛋白运输对神经损伤诱导的超敏反应的贡献 在涉及解剖学和生物化学技术的三个特定目标下描述的一系列实验中， (Aim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 神经损伤诱导的三叉神经轴突中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的治疗方法的影响。 神经性疼痛的治疗方法。沿着最先进的设施， 匹兹堡大学神经科学中心的协作环境将确保 成功完成了所提出的实验。这些研究还将为我提供技术和 智力训练需要成为一个独立的研究者在疼痛领域，而承诺， CNUP的多样性将使我能够追求促进科学包容性的职业目标。

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.