Axonal translation as a novel mechanism of nociceptor plasticity

摘要： 虽然转录的变化引起了人们的极大关注，但蛋白质的调节 直到最近，合成才被认为是伤害感受器的重要贡献者。 可塑性(Price和Geranton，2009)。在基因表达水平上的控制 翻译为DRG神经元提供了一种快速和局部的机制，通过这种机制可以产生 参与伤害性信号放大的新蛋白质。我们假设 致过敏化合物参与伤害性感受器的翻译机制的信号传递 和它们的轴突来提高翻译的限速步骤的效率， 伸长起始。这将导致蛋白质的快速从头合成，可以 介导急性致敏，并作为积极的逆行信号，引发持久的 持续致敏的基因表达的变化。我们的初步调查结果表明 促伤害性细胞因子白介素6(IL-6)刺激翻译介导 ERK-MNK通路激活对DRG神经元基因表达的影响 其磷酸化并激活eIF4E延伸起始复合体。我们也 表明IL-6通过这一途径导致CREB蛋白的合成 转录因子可能作为连接局部的细胞体的正逆行信号 外周IL-6对维持长时程增强的细胞核转录变化的影响 这些神经元的术语敏感化。在这项提案中，我们将解决以下问题 通过我们的具体目标提出的问题：1)IL-6如何向翻译发出信号 背根神经节神经元的机制？2)IL-6是否刺激轴突内的翻译 产生逆行信号到神经元核团？3)什么是 IL-6介导的翻译调控在IL-6诱导的急性和潜伏性伤害性感受器中的作用 体内致敏？拟议的研究将提供有关以下方面的重要信息 IL-6诱导DRG神经元及其轴突的翻译调控机制 导致伤害性感受器敏化，潜在地揭示了新的机制和新的 慢性疼痛管理的目标。

Summary: While much attention has been paid to changes in transcription, the regulation of protein synthesis has only recently been recognized as an important contributor to nociceptive plasticity (Price and Geranton, 2009). Control of gene expression at the level of translation affords DRG neurons a rapid and local mechanism through which to generate new proteins involved in the amplification of nociceptive signaling. We hypothesize that algogenic compounds engage signaling to the translational machinery in nociceptors and their axons to enhance the efficiency of the rate-limiting step of translation, elongation initiation. This would lead to the rapid, de-novo synthesis of proteins that can mediate acute sensitization and act as positive retrograde signals to elicit long-lasting changes in gene expression sustaining sensitization. Our preliminary findings indicate that the pro-nociceptive cytokine, interleukin 6 (IL-6), stimulates translation-mediated changes in gene expression in DRG neurons via activation of the ERK-MNK pathway which phosphorylates and activates the eIF4E elongation initiation complex. We also show that IL-6 leads to CREB protein synthesis via this pathway suggesting that this transcription factor may act as a positive retrograde signal to the cell body linking local IL-6 effects in the periphery to transcriptional changes in the nucleus sustaining long- term sensitization of these neurons. In this proposal we will address the following questions through our specific aims: 1) How does IL-6 signal to the translation machinery in DRG neurons? 2) Does IL-6 stimulate translation within the axonal compartment to generate retrograde signaling to the neuronal nucleus? 3) What is the role of IL-6-mediated translation control in IL-6-induced acute and latent nociceptor sensitization in vivo? The proposed research will provide essential information on mechanisms of IL-6-induced translation regulation in DRG neurons and their axons leading to nociceptor sensitization, potentially unveiling new mechanisms and new targets for the management of chronic pain.