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Underlying mechanisms of obesity-induced obstructive sleep apnea

Award Number: R01HL148436
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Underlying mechanisms of obesity-induced obstructive sleep apnea - Abstract Obstructive sleep apnea (OSA) is a highly prevalent disease with major neurocognitive and cardiometabolic sequelae. Obesity is a major risk factor for OSA, but the underlying mechanisms remain unclear. Given the rising prevalence of obesity and the lack of adequate therapies for some afflicted patients, further mechanistic work is clearly required. In a study led by the PI recently published in NEJM, Tirzepatide has been shown to improve OSA in people with obesity, although residual apnea was still present in some cases. OSA can occur due to several major pathophysiological factors including compromised pharyngeal anatomy, pharyngeal dilator muscle dysfunction, unstable ventilatory control (elevated loop gain), low end-expiratory lung volume and low arousal threshold. As a result, considerable complexity exists in the obesity/OSA relationship, suggesting the need for further research. Although endotypic and phenotypic variability in OSA is well established, there is controversy regarding techniques to assess OSA endotypes. Thus, for this application, we are focusing on predictors of therapeutic interventions which are likely to be guided by underlying mechanisms of OSA. We and others have reported a number of pharmacological interventions to address underlying mechanisms of OSA, but most have shown incomplete responses likely as a result of residual anatomical compromise. Thus, in three separate aims, we plan to assess the impact of acetazolamide for control of breathing (to stabilize breathing), eszopiclone for low arousal threshold and the combination of acetazolamide with eszopiclone in tirzepatide treated patients with residual OSA. The proposed studies will provide mechanistic insight into residual OSA regardless of the results. We also plan sophisticated analyses including deep learning and unsupervised clustering to determine predictors of pharmacological response. Thus, we are optimistic that we will be able to eliminate OSA pharmacologically in at least a subset of OSA patients. As a result of the proposed research, we are confident that we will gain major insights into the as yet unanswered question “why does obesity (sometimes) cause sleep apnea and why does weight loss improve but not eliminate OSA in many patients”. This research will have major therapeutic implications as it will allow us to individualize therapy for afflicted patients. Moreover it will lay the groundwork for a robust multicenter trial to treat OSA pharmacologically with a goal of improving hard outcomes.


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: 2026 ( Subtotal = $799,109 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	National Center on Sleep Disorders Research	000	5	7/3/2026	COMPETING CONTINUATION	$799,109
														Subtotal = $799,109

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	National Center on Sleep Disorders Research	000	4	9/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $651,701 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	National Center on Sleep Disorders Research	000	4	5/25/2023	NON-COMPETING CONTINUATION	$651,701
														Subtotal = $651,701

Issue Date FY: 2022 ( Subtotal = $651,701 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	National Center on Sleep Disorders Research	000	3	6/4/2022	NON-COMPETING CONTINUATION	$651,701
														Subtotal = $651,701

Issue Date FY: 2021 ( Subtotal = $651,185 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	National Center on Sleep Disorders Research	000	2	5/12/2021	NON-COMPETING CONTINUATION	$651,185
														Subtotal = $651,185

Issue Date FY: 2020 ( Subtotal = $654,364 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	National Center on Sleep Disorders Research	000	1	5/29/2020	NEW	$654,364
														Subtotal = $654,364

Grand Total All Awards = $3,408,060

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Underlying mechanisms of obesity-induced obstructive sleep apnea

Award Number: R01HL148436

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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