Axonal translation as a novel mechanism of nociceptor plasticity

描述（由申请人提供）：虽然对转录的变化给予了很大关注，但蛋白质合成的调节直到最近才被认为是伤害性可塑性的重要贡献者（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，通过该机制产生参与伤害性信号放大的新蛋白质。我们推测，致痛化合物参与信号传导到伤害感受器及其轴突的翻译机制，以提高翻译的限速步骤，延长起始的效率。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，并作为正逆行信号引起维持致敏的基因表达的持久变化。我们的初步研究结果表明，亲伤害性细胞因子，白细胞介素6（IL-6），通过激活ERK-MNK途径，磷酸化和激活eIF 4 E延伸起始复合物，刺激DRG神经元中的基因表达的抑制介导的变化。我们还表明，IL-6导致CREB蛋白合成通过这一途径，这表明该转录因子可能作为一个积极的逆行信号的细胞体连接局部IL-6的影响，在周边的转录变化，在核维持长期敏化这些神经元。在这个提议中，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神经元中的翻译机制发出信号？2)IL-6是否刺激轴突隔室内的翻译以产生到神经元核的逆行信号？3)IL-6介导的翻译控制在IL-6诱导的急性和潜伏性伤害感受器致敏中的作用是什么？拟议的研究将提供有关DRG神经元及其轴突中IL-6诱导的翻译调节机制的重要信息，从而导致伤害感受器敏化，可能揭示慢性疼痛管理的新机制和新靶点。 公共卫生相关性：慢性疼痛是一个主要的临床问题，治疗存在重大障碍。损伤或疾病后基因表达的变化是疼痛慢性化的已知原因，但对这些影响的机制知之甚少。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.