Axonal translation as a novel mechanism of nociceptor plasticity

描述（由申请人提供）：虽然很多人都关注转录的变化，但直到最近才认识到蛋白质合成的调节是伤害性可塑性的重要因素（Price and Geranton, 2009）。在翻译水平上对基因表达的控制为DRG神经元提供了一种快速和局部的机制，通过该机制产生参与伤害性信号扩增的新蛋白质。我们假设，致痛化合物参与到伤害感受器及其轴突的翻译机制的信号传导中，以提高翻译的限速步骤，即延伸起始的效率。这将导致蛋白质的快速、从头合成，这些蛋白质可以介导急性致敏，并作为积极的逆行信号，引发维持致敏的基因表达的长期变化。我们的初步研究结果表明，促伤害细胞因子白介素6 （IL-6）通过激活ERK-MNK通路刺激DRG神经元中翻译介导的基因表达变化，ERK-MNK通路磷酸化并激活eIF4E延伸起始复合物。我们还表明，IL-6通过这一途径导致CREB蛋白的合成，这表明该转录因子可能作为细胞体的正向逆行信号，将外周局部IL-6效应与维持这些神经元长期敏化的细胞核转录变化联系起来。在本提案中，我们将通过我们的具体目标解决以下问题：1)IL-6如何向DRG神经元的翻译机制发出信号？2) IL-6是否刺激轴突腔室内的翻译从而向神经元核产生逆行信号？3) il -6介导的翻译调控在体内il -6诱导的急性和潜伏伤害感受器致敏中的作用是什么？该研究将提供il -6诱导DRG神经元及其轴突翻译调控导致伤害感受器致敏的机制的重要信息，可能揭示慢性疼痛管理的新机制和新靶点。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Chronic pain is a major clinical problem with significant barriers to treatment. Changes in gene expression upon injury or disease are known causes for the chronification of pain but mechanisms underlying these effects are poorly understood. Through this research, we intend to discover novel mechanisms of regulation of gene expression, linked to translation control, which will enhance our understanding of how pain becomes chronic and potentially lead to the discovery of novel treatment avenues.