Axonal translation as a novel mechanism of nociceptor plasticity

总结： 虽然人们对转录的变化给予了很多关注，但蛋白质的调节 合成只是最近才被认为是伤害感受性的重要贡献者。 可塑性（Price和Geranton，2009）。基因表达水平的调控 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， 参与伤害性信号放大的新蛋白质。我们假设 致痛化合物将信号传递到伤害感受器中的翻译机制 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， 介导急性致敏，并作为积极的逆行信号， 基因表达的变化维持致敏。我们的初步调查结果显示 促伤害性细胞因子白细胞介素6（IL-6）刺激免疫介导的 通过激活ERK-MNK通路改变DRG神经元中的基因表达 其磷酸化并激活eIF 4 E延伸起始复合物。我们也 表明IL-6通过该途径导致CREB蛋白合成，这表明 转录因子可以作为一个积极的逆行信号，细胞体连接局部 IL-6在外周对细胞核中转录变化的影响持续了长时间， 这些神经元的长期敏感化。在本提案中，我们将解决以下问题 通过我们的具体目标的问题：1）如何IL-6的信号翻译 背根神经节神经元中的机械2)IL-6是否刺激轴突内的翻译 隔室产生逆行信号到神经元核？3)是什么 IL-6介导的翻译调控在IL-6诱导的急性和潜伏性伤害感受器中的作用 体内致敏？拟议的研究将提供以下方面的重要信息： IL-6诱导DRG神经元及其轴突翻译调控的机制 导致伤害感受器敏感化，潜在地揭示新的机制和新的 治疗慢性疼痛的目标。

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.