Chronic Intermittent Hypoxia and Hyperalgesic Priming

慢性间歇性缺氧和痛觉过敏引发

基本信息

项目摘要

PROJECT SUMMARY Sleep is critical to health and well-being, such that current trends towards reduced sleep time and quality, coupled with rising diagnoses of sleep disorders, negatively affect multiple physiological systems. Increasing clinical evidence indicates that sleep disorders such as obstructive sleep apnea (OSA) contribute to chronic pain, with over 40% of sleep disordered patients reporting chronic pain conditions. However, there is a gap in knowledge concerning how disorders such as intermittent hypoxia contribute to persistent pain. Our long-term goal is to reduce persistent pain in patients experiencing sleep disorders. As we work towards this goal, the overall objective of this application is to define the mechanism by which intermittent hypoxia contributes to the transition from acute-to-chronic pain. Our central hypothesis is that hypoxia from sleep disorders produces neuroimmune hyperalgesic priming via peripheral macrophage up-regulation. We propose that chronic intermittent hypoxia stimulates macrophage polarization to increase inflammatory cytokine production in peripheral nociceptive tissues. Our hypothesis is based on strong evidence utilizing an innovative rodent model for chronic intermittent hypoxia (CIH) that mimics OSA. The rationale for this work is that increasing our mechanistic understanding of how intermittent hypoxia contributes to persistent pain could improve quality of life for tens of millions of American that suffer from sleep disorders. To accomplish our objective, we will test our central hypothesis with the following related, yet interdependent aims: (1) Identify the location of neuroimmune interaction, (2) Interrogate the distribution and role of M1/M2 macrophage polarization, and (3) Examine hypoxic activation of peripheral macrophages. We propose a multi-disciplinary approach to testing our hypothesis, utilizing transgenic and Cre-Lox recombination mice in biochemical, pharmacological, in vivo imaging and behavioral protocols with FACS cell sorting and RNA profiling in tandem. Our CIH treatment paradigm is highly innovative for its translational relevance to human OSA, as is our molecular and biochemical profiling of resident and infiltrating macrophage populations in hyperalgesic priming. The proposed research is significant because it will identify novel mechanisms by which sleeping disorders contribute to persistent pain.
项目摘要 睡眠对健康和幸福至关重要,因此目前睡眠时间和质量减少的趋势, 再加上越来越多的睡眠障碍的诊断,对多个生理系统产生负面影响。增加 临床证据表明睡眠障碍如阻塞性睡眠呼吸暂停(OSA)导致慢性疼痛, 超过40%的睡眠障碍患者报告慢性疼痛状况。然而,在以下方面存在差距: 了解间歇性缺氧等疾病如何导致持续性疼痛。我们的长期 目标是减少睡眠障碍患者的持续疼痛。当我们朝着这个目标努力时, 本申请的总体目标是定义间歇性缺氧有助于 从急性疼痛到慢性疼痛的转变。我们的中心假设是睡眠障碍引起的缺氧 通过外周巨噬细胞上调的神经免疫痛觉过敏引发。我们建议,慢性 间歇性低氧刺激巨噬细胞极化增加炎症细胞因子的产生, 外周伤害感受组织我们的假设是基于强有力的证据,利用创新的啮齿动物模型 慢性间歇性缺氧(CIH)模拟OSA。这项工作的基本原理是,增加我们的 对间歇性缺氧如何导致持续性疼痛的机械理解可以改善生活质量 为数千万患有睡眠障碍的美国人。为了实现我们的目标,我们将测试我们的 中心假设与以下相关,但相互依存的目标:(1)确定神经免疫的位置 相互作用,(2)询问M1/M2巨噬细胞极化的分布和作用,和(3)检查缺氧 激活外周巨噬细胞。我们提出了一个多学科的方法来测试我们的假设, 利用转基因和Cre-Lox重组小鼠进行生物化学、药理学、体内成像, 行为方案与串联的FACS细胞分选和RNA分析。我们的CIH治疗模式高度 创新的翻译相关性,人类OSA,因为是我们的分子和生化分析居民 以及在痛觉过敏引发中的浸润巨噬细胞群体。这项研究意义重大,因为 它将确定睡眠障碍导致持续疼痛的新机制。

项目成果

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NATHANIEL Aaron JESKE其他文献

NATHANIEL Aaron JESKE的其他文献

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{{ truncateString('NATHANIEL Aaron JESKE', 18)}}的其他基金

Chronic Intermittent Hypoxia and Hyperalgesic Priming - Administrative Supplement
慢性间歇性缺氧和痛觉过敏启动 - 行政补充
  • 批准号:
    10844191
  • 财政年份:
    2023
  • 资助金额:
    $ 62.93万
  • 项目类别:
Scaffolding Opiate Analgesia
支架阿片镇痛
  • 批准号:
    9164537
  • 财政年份:
    2016
  • 资助金额:
    $ 62.93万
  • 项目类别:
Scaffolding the Transition to Chronic Pain
搭建向慢性疼痛过渡的脚手架
  • 批准号:
    9263031
  • 财政年份:
    2013
  • 资助金额:
    $ 62.93万
  • 项目类别:
Scaffolding the Transition to Chronic Pain
搭建向慢性疼痛过渡的脚手架
  • 批准号:
    8664950
  • 财政年份:
    2013
  • 资助金额:
    $ 62.93万
  • 项目类别:
Scaffolding the Transition to Chronic Pain
搭建向慢性疼痛过渡的脚手架
  • 批准号:
    8687906
  • 财政年份:
    2013
  • 资助金额:
    $ 62.93万
  • 项目类别:
Scaffolding the Transition to Chronic Pain
搭建向慢性疼痛过渡的脚手架
  • 批准号:
    8577841
  • 财政年份:
    2013
  • 资助金额:
    $ 62.93万
  • 项目类别:
Scaffolding the Transition to Chronic Pain
搭建向慢性疼痛过渡的脚手架
  • 批准号:
    9052231
  • 财政年份:
    2013
  • 资助金额:
    $ 62.93万
  • 项目类别:
AKAP MODULATES TRPV1 PHOSPHORYLATION AND SENSITIZATION
AKAP 调节 TRPV1 磷酸化和致敏
  • 批准号:
    8049940
  • 财政年份:
    2008
  • 资助金额:
    $ 62.93万
  • 项目类别:
AKAP MODULATES TRPV1 PHOSPHORYLATION AND SENSITIZATION
AKAP 调节 TRPV1 磷酸化和敏化
  • 批准号:
    7643087
  • 财政年份:
    2008
  • 资助金额:
    $ 62.93万
  • 项目类别:
AKAP MODULATES TRPV1 PHOSPHORYLATION AND SENSITIZATION
AKAP 调节 TRPV1 磷酸化和致敏
  • 批准号:
    7531592
  • 财政年份:
    2008
  • 资助金额:
    $ 62.93万
  • 项目类别:

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