Chronic Intermittent Hypoxia and Hyperalgesic Priming

慢性间歇性缺氧和痛觉过敏引发

基本信息

批准号：
10655935
负责人：
NATHANIEL Aaron JESKE
金额：
$ 62.93万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10655935
关键词：
Abate Affect Afferent Neurons American Anti-Inflammatory Agents Behavior Behavioral Biochemical Biological Assay Cell Separation Chronic Clinical Clinical Research Complement Continuous Positive Airway Pressure Coupled Cre lox recombination system DNA Binding Development Diagnosis Disease Future Genetic Screening Goals Health Human Hypoxia Image Immune In Vitro Infiltration Inflammatory Knowledge Link Location Macrophage Maintenance Measures Mission Modeling Molecular Molecular Genetics Mus Neuroimmune Neuronal Plasticity Neurons Nociception Nociceptors Obstructive Sleep Apnea Oxidative Stress Pain Pathogenicity Patients Peripheral Persistent pain Personal Satisfaction Pharmacology Study Pharmacotherapy Phase Phenotype Physiological Pilot Projects Population Production Protocols documentation Public Health Quality of life RNA Recurrence Reporting Research Rodent Rodent Model Role Signal Pathway Sleep Sleep Disorders Sleep disturbances System Testing Time Tissues Transcript Transgenic Organisms Translating United States National Institutes of Health Up-Regulation Work chronic pain chronic painful condition clinical diagnosis comorbidity cytokine experience health determinants hypoxia inducible factor 1 improved in vivo in vivo imaging inducible Cre innovation interdisciplinary approach molecular marker multidisciplinary nanoGold nanoparticle drug negative affect nocturnal Hypoxemia novel pain behavior pain chronification pain sensation pharmacologic preclinical study trend

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.

项目概要睡眠对于健康和福祉至关重要，因此当前的趋势是减少睡眠时间和质量，再加上睡眠障碍的诊断不断增加，对多个生理系统产生负面影响。增加临床证据表明，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症状。然而，存在差距关于间歇性缺氧等疾病如何导致持续性疼痛的知识。我们的长期目标是减少睡眠障碍患者的持续疼痛。当我们努力实现这一目标时，该应用的总体目标是确定间歇性缺氧导致从急性疼痛转变为慢性疼痛。我们的中心假设是睡眠障碍导致的缺氧会产生通过外周巨噬细胞上调引发神经免疫痛觉过敏。我们建议慢性间歇性缺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。我们的假设基于利用创新啮齿动物模型的有力证据用于模拟 OSA 的慢性间歇性缺氧 (CIH)。这项工作的基本原理是增加我们的了解间歇性缺氧如何导致持续性疼痛的机制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，我们将测试我们的中心假设具有以下相关但相互依赖的目标：（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，以及 (3) 检查缺氧外周巨噬细胞的激活。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、药理学、体内成像和结合 FACS 细胞分选和 RNA 分析的行为方案。我们的 CIH 治疗模式高度因其与人类 OSA 的转化相关性而具有创新性，我们对居民的分子和生化分析也是如此以及在痛觉过敏引发中渗透巨噬细胞群。拟议的研究意义重大，因为它将确定睡眠障碍导致持续性疼痛的新机制。