# Circadian Clock Dysregulation in a Model of Obstructive Sleep Apnea

> **NIH NIH K08** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $163,607

## Abstract

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.

## Key facts

- **NIH application ID:** 9996778
- **Project number:** 5K08HL148551-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** David F Smith
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $163,607
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996778

## Citation

> US National Institutes of Health, RePORTER application 9996778, Circadian Clock Dysregulation in a Model of Obstructive Sleep Apnea (5K08HL148551-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9996778. Licensed CC0.

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