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: 7884087
• 负责人: Theodore J. Price
• 金额: $ 32.72万
• 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/7884087
• 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; Neuropathy; Nociception; Nociceptors; Pain; Pathway interactions; Peptide Initiation Factors; Peripheral; Phosphorylation; Phosphotransferases; Play; Price; Process; Protein Biosynthesis; 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; 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）：虽然对转录变化的关注非常关注，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 and Geranton，2009年）。控制基因表达在翻译水平上提供了DRG神经元的快速和局部机制，通过该机制，通过该机制产生与伤害性信号扩增有关的新蛋白质。我们假设算法化合物将信号传递到伤害感受器及其轴突的转换机械，以提高翻译速率限制步骤的效率。这将导致蛋白质的快速，脱离蛋白质的快速合成，这些蛋白质可以介导急性敏化并充当阳性逆行信号，从而引起持续敏化的基因表达的持久变化。我们的初步发现表明，促核细胞因子白细胞因子6（IL-6）通过激活ERK-MNK途径刺激DRG神经元中基因表达的转化介导的变化，ERK-MNK途径磷酸化并激活EIF4E EIF4E延长启动启动复合物。我们还表明，IL-6通过该途径导致CREB蛋白合成，这表明该转录因子可能充当呈正的逆行信号，与连接到周围局部IL-6效应的细胞体的正向信号与维持这些神经元长期长期致敏的核的转录变化相关。在此提案中，我们将通过我们的具体目的解决以下问题：1）IL-6向DRG神经元中的翻译机械发出信号？ 2）IL-6是否刺激轴突隔室内的翻译以产生向神经元核的逆行信号？ 3）IL-6介导的翻译控制在IL-6诱导的急性和潜在伤害感受器在体内的作用是什么？拟议的研究将提供有关DRG神经元中IL-6诱导的翻译调节机制及其轴突的基本信息，导致伤害感受器的敏化，潜在地揭示了新的机制以及用于管理慢性疼痛的新目标。 公共卫生相关性：慢性疼痛是一个主要的临床问题，具有重大治疗障碍。损伤或疾病时基因表达的变化是疼痛编年期的已知原因，但这些作用的机制对这些作用的理解很少。通过这项研究，我们打算发现与翻译控制有关的基因表达调节的新型机制，这将增强我们对疼痛如何变得慢性的理解，并可能导致发现新的治疗途径。