Chronic Intermittent Hypoxia and Hyperalgesic Priming

项目总结 睡眠对健康和幸福至关重要，因此，目前睡眠时间和质量下降的趋势， 再加上睡眠障碍的诊断率上升，对多个生理系统产生了负面影响。渐增 临床证据表明，阻塞性睡眠呼吸暂停(OSA)等睡眠障碍会导致慢性疼痛， 超过40%的睡眠障碍患者报告有慢性疼痛状况。然而，有一个缺口是在 关于间歇性低氧等疾病如何导致持续性疼痛的知识。我们的长期合作 目标是减少睡眠障碍患者的持续性疼痛。在我们朝着这一目标努力的过程中， 本应用的总体目标是确定间歇性低氧对 从急性疼痛过渡到慢性疼痛。我们的中心假设是睡眠障碍引起的缺氧会产生 通过外周巨噬细胞上调的神经免疫痛觉过敏启动。我们建议慢性 间歇性低氧刺激巨噬细胞极化增加炎性细胞因子的产生 外周伤害性组织。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 用于模拟OSA的慢性间歇性低氧(CIH)。这项工作的基本原理是增加我们的 对间歇性低氧如何导致持续性疼痛的机械性理解可以改善生活质量 对于数千万患有睡眠障碍的美国人来说。为了实现我们的目标，我们将测试我们的 具有以下相关但相互依赖的目的的中心假设：(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，以及(3)检查低氧 激活外周巨噬细胞。我们提出了一种多学科方法来检验我们的假设， 利用转基因和Cre-Lox重组小鼠进行生化、药理、体内成像和 与FACS细胞分类和RNA分析同步进行的行为协议。我们的CIH治疗模式高度 创新的是它与人类OSA的翻译相关性，我们的居民的分子和生化图谱也是如此 痛觉过敏时巨噬细胞群的渗入。这项拟议的研究具有重要意义，因为 它将确定睡眠障碍导致持续性疼痛的新机制。

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.