Axonal translation as a novel mechanism of nociceptor plasticity

轴突翻译作为伤害感受器可塑性的新机制

• 批准号: 8039914
• 负责人: Theodore J. Price
• 金额: $ 32.08万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039914
• 关键词: Acute; Address; Afferent Neurons; Animal Model; Attention; Axon; Behavioral; Behavioral Model; Biochemical; Biological Models; CREB1 gene; Cell Nucleus; Cells; Chronic; Clinical; Complex; Confocal Microscopy; Cyclic AMP-Responsive DNA-Binding Protein; Data; Disease; Gene Expression; Gene Expression Regulation; Goals; Human Pathology; Hyperalgesia; Immunohistochemistry; In Vitro; Inflammatory; Injury; Interleukin-6; Laboratories; Lead; Learning; Link; Mediating; Mediator of activation protein; Memory; Microfluidic Microchips; Natural regeneration; Neuronal Plasticity; Neurons; Nociception; Nociceptors; Pain; Pathway interactions; Peptide Initiation Factors; Peripheral; Phosphorylation; Phosphotransferases; Play; Price; Process; Protein Biosynthesis; Protein Inhibition; Protein Synthesis Inhibition; Proteins; Recruitment Activity; Regulation; Research; Ribosomal Proteins; Role; Sensory Ganglia; Signal Pathway; Signal Transduction; Synaptic plasticity; System; Testing; Therapeutic; Transcriptional Regulation; Translations; behavioral pharmacology; cancer pain; chronic pain; cytokine; design; extracellular; in vivo; neuron development; neuronal cell body; neuronal excitability; novel; painful neuropathy; public health relevance; research study; retrograde transport; transcription factor

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.

描述（由申请人提供）：虽然转录的变化受到了很多关注，但蛋白质合成的调节直到最近才被认为是伤害感受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且局部的机制，通过该机制生成参与放大伤害性信号传导的新蛋白质。我们假设致痛化合物参与伤害感受器及其轴突中翻译机制的信号传导，以提高翻译限速步骤、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，并充当正逆行信号，引发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，促伤害性细胞因子白细胞介素 6 (IL-6) 通过激活 ERK-MNK 通路（磷酸化并激活 eIF4E 延伸起始复合物），刺激 DRG 神经元中翻译介导的基因表达变化。我们还表明，IL-6 通过该途径导致 CREB ​​蛋白合成，表明该转录因子可能作为细胞体的正逆行信号，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中的转录变化联系起来。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 神经元中的翻译机制发出信号？ 2) IL-6 是否刺激轴突区室内的翻译以产生向神经元核的逆行信号传导？ 3) IL-6介导的翻译控制在IL-6诱导的体内急性和潜在伤害感受器敏化中的作用是什么？拟议的研究将提供有关 DRG 神经元及其轴突中 IL-6 诱导的翻译调节导致伤害感受器敏化的机制的重要信息，有可能揭示慢性疼痛管理的新机制和新目标。 公共卫生相关性：慢性疼痛是一个重大的临床问题，对治疗存在重大障碍。损伤或疾病时基因表达的变化是导致疼痛慢性化的已知原因，但人们对这些影响背后的机制知之甚少。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变成慢性的理解，并可能导致新治疗途径的发现。