Circadian Clock Dysregulation in a Model of Obstructive Sleep Apnea

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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.