Axonal translation as a novel mechanism of nociceptor plasticity

描述(申请人提供)：虽然转录的变化受到了很大的关注，但蛋白质合成的调控直到最近才被认为是伤害性可塑性的重要贡献因素(Price和Geranton，2009)。在翻译水平上控制基因表达为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。我们假设致敏化合物参与伤害性感受器及其轴突中的翻译机制的信号传递，以提高翻译的限速步骤-伸长起始的效率。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。我们的初步发现表明，促伤害性细胞因子白介素6(IL-6)通过激活ERK-MNK通路来刺激翻译介导的DRG神经元基因表达的变化，ERK-MNK通路磷酸化并激活eIF4E延长起始复合体。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，将外围局部的IL-6效应与维持这些神经元长期敏化的细胞核的转录变化联系起来。在这个提案中，我们将通过我们的具体目标来解决以下问题：1)IL-6如何向DRG神经元的翻译机制发送信号？2)IL-6是否刺激轴突室内的翻译以产生逆行信号到神经元核团？3)IL-6介导的翻译控制在IL-6诱导的急性和潜伏性伤害性感受器敏化中起什么作用？这项拟议的研究将为IL-6诱导的DRG神经元及其轴突的翻译调节导致伤害性感受器敏化的机制提供重要信息，可能为慢性疼痛的治疗提供新的机制和新的靶点。 公共卫生相关性：慢性疼痛是一个主要的临床问题，治疗上存在重大障碍。受伤或疾病时基因表达的变化是疼痛慢性化的已知原因，但这些影响背后的机制尚不清楚。通过这项研究，我们打算发现与翻译控制相关的基因表达调控的新机制，这将增强我们对疼痛如何成为慢性疼痛的理解，并可能导致发现新的治疗途径。

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.