Circadian Clock Dysregulation in a Model of Obstructive Sleep Apnea

阻塞性睡眠呼吸暂停模型中的昼夜节律失调

• 批准号: 10218268
• 负责人: David F Smith
• 金额: $ 16.36万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218268
• 关键词: ATAC-seq; Affect; Biology; Blood Pressure; Cardiopulmonary; Cardiovascular system; Cells; ChIP-seq; Child; Chromatin; Circadian Dysregulation; Clock protein; DNA; Data; Dependence; Development; Disease; Dyslipidemias; Early Intervention; Event; Exposure to; Five-Year Plans; Functional disorder; Gene Expression; Genome; Heart; Heart Diseases; Hypoxia; Hypoxia Inducible Factor; Individual; Inflammatory; Injury; Knowledge; Lead; Link; Lung; Lung diseases; Measures; Medicine; Metabolic dysfunction; Modality; Modeling; Molecular; Morbidity - disease rate; Mus; Neurocognitive; Obstructive Sleep Apnea; Organ; Outcome; Oxidative Stress; Oxygen; Patients; Phase; Physiological; Physiological Processes; Play; Prevention; Problem behavior; Process; Publishing; Recovery; Research; Role; Scientist; Signal Pathway; Sleep; Sleep Architecture; Structure of parenchyma of lung; Surgeon; Testing; Time; Up-Regulation; Work; airway obstruction; base; burden of illness; cardiopulmonary system; career development; cell type; circadian; circadian pacemaker; endothelial dysfunction; genome-wide; inflammatory marker; innovation; laboratory experience; male; molecular clock; mouse model; novel therapeutics; response; sex; single-cell RNA sequencing; targeted treatment; transcription factor; transcriptome sequencing

ABSTRACT Obstructive sleep apnea (OSA) occurs in 4% of children in the US. OSA is characterized by upper airway obstruction and intermittent hypoxia during sleep. Even in young children, untreated OSA can lead to heart and lung conditions, metabolic dysfunction, and neurocognitive problems. Without early intervention, these pathophysiologic changes may lead to a lifetime burden of disease. The disease processes associated with OSA are driven by upregulation of inflammatory mechanisms, heightened oxidative stress, and endothelial dysfunction. Despite our understanding of OSA and intermittent hypoxia, the upstream causal events remain poorly characterized. An emerging hypothesis to explain other hypoxic-driven diseases is that low oxygen levels reset the circadian clock. Hypoxia inducible factors (HIFs) are transcription factors that are stabilized under low oxygen conditions to activate an array of physiologic processes. These factors also communicate with the molecular clock at the genome level. The link between hypoxia and the circadian clock may be an important, though unexplored mechanism by which OSA leads to associated disease processes in the cardiopulmonary system. I hypothesize that intermittent hypoxia results in circadian clock dysregulation, resulting in molecular mechanisms that contribute to end-organ damage. I will pursue this hypothesis by (1) determining the impact of circadian phase on physiologic responses to intermittent hypoxia and recovery (IHR) as a model for OSA, (2) characterizing the sex-dependency of IHR on mechanisms of end-organ damage, and (3) identifying specific cardiopulmonary cell types that respond to IHR. Collectively, this work may enable new management strategies and targeted therapies for OSA based on realignment of the circadian clock. In this proposal, I present a five-year plan for career development focused on didactic coursework and hands-on laboratory experience. The research strategy and didactic work will help me to become an independent surgeon-scientist, pursuing innovative discoveries in the field of sleep medicine.

摘要 阻塞性睡眠呼吸暂停(OSA)在美国4%的儿童中发生。OSA的特点是 睡眠时上呼吸道阻塞和间歇性低氧。即使是在年幼的儿童中， 未经治疗的OSA可导致心肺疾病、代谢功能障碍和神经认知 有问题。如果不及早干预，这些病理生理变化可能导致终生。 疾病的负担。 与OSA相关的疾病过程是由炎症的上调驱动的 机制、氧化应激加剧和内皮功能障碍。尽管我们 了解OSA和间歇性低氧，上游原因事件仍然较差 特色化的。一个新出现的解释其他由缺氧引起的疾病的假说是 氧气水平重置了生物钟。低氧诱导因子是一类转录因子 它们在低氧条件下稳定下来，以激活一系列生理过程。 这些因子也在基因组水平上与分子时钟通信。 然而，低氧和生物钟之间的联系可能是一个重要的 阻塞性睡眠呼吸暂停综合征导致相关疾病过程的未知机制 心肺系统。我假设间歇性低氧会导致生物钟 调节失调，导致导致终末器官损伤的分子机制。我 将通过(1)确定昼夜节律对生理的影响来进一步研究这一假说 间歇性低氧和恢复(IHR)作为阻塞性睡眠呼吸暂停综合征模型的反应，(2)表征 IHR对终末器官损伤机制的性别依赖性，以及(3)识别特定的 对IHR有反应的心肺细胞类型。总的来说，这项工作可能会使新的 基于昼夜节律调整的阻塞性睡眠呼吸暂停的治疗策略和靶向治疗 钟。 在这份提案中，我提出了一个职业发展的五年计划，重点是说教 具有课程作业和实验室实践经验。研究策略和教学工作将 帮助我成为一名独立的外科医生兼科学家，在 睡眠医学领域。