Circadian Clock Dysregulation in a Model of Obstructive Sleep Apnea

摘要 阻塞性睡眠呼吸暂停（OSA）发生在4%的儿童在美国。OSA的特征在于： 睡眠时上呼吸道阻塞和间歇性缺氧。即使是小孩子， 未经治疗的OSA可导致心肺疾病、代谢功能障碍和神经认知障碍。 问题如果不早期干预，这些病理生理变化可能导致终生 疾病负担。 与OSA相关的疾病过程是由炎症因子的上调驱动的。 机制，氧化应激增强和内皮功能障碍。尽管我们 对OSA和间歇性缺氧的理解，上游因果事件仍然很差 表征了一个新出现的假说来解释其他缺氧驱动的疾病是， 氧气水平会重置生物钟缺氧诱导因子是一类转录因子 在低氧条件下稳定，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钟进行通信。 缺氧和生物钟之间的联系可能是一个重要的， OSA导致相关疾病过程的未探索机制 心肺系统我假设间歇性缺氧导致生物钟 失调，导致有助于终末器官损伤的分子机制。我 将通过（1）确定昼夜节律相位对生理节律的影响来实现这一假设。 对间歇性缺氧和恢复（IHR）的反应作为OSA的模型，（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，这项工作可以使新的 基于昼夜节律调整的OSA管理策略和靶向治疗 时钟 在这份提案中，我提出了一个五年职业发展计划，重点是教学 课程作业和动手实验室经验。研究战略和教学工作将 帮助我成为一个独立的外科医生，科学家，追求创新的发现， 睡眠医学领域。

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.