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Circadian Clock Dysregulation in a Model of Obstructive Sleep Apnea

Award Number: K08HL148551
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Circadian Clock Dysregulation in a Model of Obstructive Sleep Apnea - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$40,064 )
2025	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	National Center on Sleep Disorders Research	000	5	11/22/2024	NON-COMPETING CONTINUATION	-$40,064
														Subtotal = -$40,064

Issue Date FY: 2023 ( Subtotal = $163,539 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	National Center on Sleep Disorders Research	000	5	5/24/2023	NON-COMPETING CONTINUATION	$163,539
														Subtotal = $163,539

Issue Date FY: 2022 ( Subtotal = $163,458 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	National Center on Sleep Disorders Research	000	4	6/10/2022	NON-COMPETING CONTINUATION	$163,458
														Subtotal = $163,458

Issue Date FY: 2021 ( Subtotal = $163,583 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	National Center on Sleep Disorders Research	000	3	8/4/2021	NON-COMPETING CONTINUATION	$163,583
														Subtotal = $163,583

Issue Date FY: 2020 ( Subtotal = $163,607 )
2020	2020	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	National Center on Sleep Disorders Research	000	2	7/16/2020	NON-COMPETING CONTINUATION	$163,607
														Subtotal = $163,607

Issue Date FY: 2019 ( Subtotal = $163,579 )
2019	2019	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	National Center on Sleep Disorders Research	000	1	8/15/2019	NEW	$163,579
														Subtotal = $163,579

Grand Total All Awards = $777,702

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Circadian Clock Dysregulation in a Model of Obstructive Sleep Apnea

Award Number: K08HL148551

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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