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

基本信息

  • 批准号:
    8436244
  • 负责人:
  • 金额:
    $ 36.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-03-15 至 2014-03-01
  • 项目状态:
    已结题

项目摘要

Summary: 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.
总结: 虽然人们对转录的变化给予了很多关注,但蛋白质的调节 合成只是最近才被认为是伤害感受性的重要贡献者。 可塑性(Price和Geranton,2009)。基因表达水平的调控 翻译为DRG神经元提供了一种快速和局部的机制,通过这种机制, 参与伤害性信号放大的新蛋白质。我们假设 致痛化合物将信号传递到伤害感受器中的翻译机制 和它们的轴突来提高翻译的限速步骤的效率, 伸长起始这将导致蛋白质的快速从头合成, 介导急性致敏,并作为积极的逆行信号, 基因表达的变化维持致敏。我们的初步调查结果显示 促伤害性细胞因子白细胞介素6(IL-6)刺激免疫介导的 通过激活ERK-MNK通路改变DRG神经元中的基因表达 其磷酸化并激活eIF 4 E延伸起始复合物。我们也 表明IL-6通过该途径导致CREB蛋白合成,这表明 转录因子可以作为一个积极的逆行信号,细胞体连接局部 IL-6在外周对细胞核中转录变化的影响持续了长时间, 这些神经元的长期敏感化。在本提案中,我们将解决以下问题 通过我们的具体目标的问题:1)如何IL-6的信号翻译 背根神经节神经元中的机械2)IL-6是否刺激轴突内的翻译 隔室产生逆行信号到神经元核?3)是什么 IL-6介导的翻译调控在IL-6诱导的急性和潜伏性伤害感受器中的作用 体内致敏?拟议的研究将提供以下方面的重要信息: IL-6诱导DRG神经元及其轴突翻译调控的机制 导致伤害感受器敏感化,潜在地揭示新的机制和新的 治疗慢性疼痛的目标。

项目成果

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Theodore J. Price其他文献

Persistent nociceptor hyperactivity as a painful evolutionary adaptation
持续性伤害感受器过度活跃作为一种痛苦的进化适应
  • DOI:
    10.1016/j.tins.2022.12.007
  • 发表时间:
    2023-03-01
  • 期刊:
  • 影响因子:
    15.100
  • 作者:
    Edgar T. Walters;Robyn J. Crook;G. Gregory Neely;Theodore J. Price;Ewan St John Smith
  • 通讯作者:
    Ewan St John Smith
Single-nuclei Ribonucleic Acid Sequencing Shows Unique Transcriptomic Signatures of Rat Dorsal Root Ganglia in a Disc-associated Chronic Low Back Pain Model
单核 RNA 测序显示在椎间盘相关慢性下腰痛模型中大鼠背根神经节的独特转录组特征
  • DOI:
    10.1016/j.jpain.2024.01.103
  • 发表时间:
    2024-04-01
  • 期刊:
  • 影响因子:
    4.000
  • 作者:
    Sydney M. Caparaso;Ishwarya Sankaranarayanan;Theodore J. Price;Rebecca A. Wachs
  • 通讯作者:
    Rebecca A. Wachs
Nerve detection and visualization using hyperspectral imaging for surgical guidance
使用高光谱成像进行神经检测和可视化以进行手术指导
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Minh H. Tran;Michelle Bryarly;Ling Ma;Muhammad Saad Yousuf;Theodore J. Price;Baowei Fei
  • 通讯作者:
    Baowei Fei
Human pain neuroscience and the next generation of pain therapeutics
人类疼痛神经科学与下一代疼痛疗法
  • DOI:
    10.1016/j.neuron.2025.04.005
  • 发表时间:
    2025-05-07
  • 期刊:
  • 影响因子:
    15.000
  • 作者:
    Bryan A. Copits;Michele Curatolo;Patrick M. Dougherty;Robert W. Gereau;Wenqin Luo;Maryann Martone;Hakan Olausson;Theodore J. Price;William Renthal;Clifford J. Woolf;Guoyan Zhao;NIH PRECISION Human Pain Network
  • 通讯作者:
    NIH PRECISION Human Pain Network
Fibroblast-derived PI16 sustains inflammatory pain via regulation of CD206sup+/sup myeloid cells
成纤维细胞衍生的 PI16 通过调节 CD206+髓样细胞维持炎症性疼痛
  • DOI:
    10.1016/j.bbi.2023.06.011
  • 发表时间:
    2023-08-01
  • 期刊:
  • 影响因子:
    7.600
  • 作者:
    Rachelle Garrity;Neha Arora;Md. Areeful Haque;Drew Weis;Ronnie T. Trinh;Sanjay V. Neerukonda;Susmita Kumari;Ibdanelo Cortez;Eroboghene E. Ubogu;Rajasekaran Mahalingam;Diana Tavares-Ferreira;Theodore J. Price;Annemieke Kavelaars;Cobi J. Heijnen;Andrew J. Shepherd
  • 通讯作者:
    Andrew J. Shepherd

Theodore J. Price的其他文献

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{{ truncateString('Theodore J. Price', 18)}}的其他基金

Mapping the human DRG and spinal cord functional genome at cellular and spatial resolution
以细胞和空间分辨率绘制人类 DRG 和脊髓功能基因组图谱
  • 批准号:
    10593658
  • 财政年份:
    2022
  • 资助金额:
    $ 36.9万
  • 项目类别:
Mapping the human DRG and spinal cord functional genome at cellular and spatial resolution
以细胞和空间分辨率绘制人类 DRG 和脊髓功能基因组图谱
  • 批准号:
    10707548
  • 财政年份:
    2022
  • 资助金额:
    $ 36.9万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10707547
  • 财政年份:
    2022
  • 资助金额:
    $ 36.9万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10593657
  • 财政年份:
    2022
  • 资助金额:
    $ 36.9万
  • 项目类别:
Young Investigator travel support for the 2016 through 2020 APS Annual Scientific Meetings
为 2016 年至 2020 年 APS 年度科学会议提供青年研究者差旅支持
  • 批准号:
    9199409
  • 财政年份:
    2016
  • 资助金额:
    $ 36.9万
  • 项目类别:
Young Investigator travel support for the 2016 through 2020 APS Annual Scientific Meetings
为 2016 年至 2020 年 APS 年度科学会议提供青年研究者差旅支持
  • 批准号:
    9121081
  • 财政年份:
    2016
  • 资助金额:
    $ 36.9万
  • 项目类别:
Young Investigator Travel Support for the 2015 APS Annual Scientific Meeting
2015 年 APS 年度科学会议青年研究员旅行支持
  • 批准号:
    8911527
  • 财政年份:
    2015
  • 资助金额:
    $ 36.9万
  • 项目类别:
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
  • 财政年份:
    2010
  • 资助金额:
    $ 36.9万
  • 项目类别:
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:
    8238358
  • 财政年份:
    2010
  • 资助金额:
    $ 36.9万
  • 项目类别:
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
  • 财政年份:
    2010
  • 资助金额:
    $ 36.9万
  • 项目类别:

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