Monday, June 30, 2025 6/30/2025

Obstructive sleep apnea, the microbiome and cardiovascular disease

Award Number: R01HL157445
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Obstructive sleep apnea, the microbiome and cardiovascular disease - ABSTRACT Obstructive sleep apnea (OSA) is a common condition affecting >10% of the adult population and 2-3% of children in the USA. OSA is considered as an independent risk factor for the development of cardiovascular and lung disorders but the underlying mechanisms are still largely unknown. In particular, the role of intermittent hypoxia and hypercapnia (IHC, the integral components of OSA) in inducing or promoting cardiovascular conditions remains obscure. Recent advances in sequencing technology and microbial and metabolomic bioinformatics have shed light on an important relation between the gut microbiome and cardiovascular diseases. Since OSA is a critical risk factor for these disorders, and our preliminary studies have demonstrated that IHC alters the ecology of gut microbiome and have a strong impact on metabolism, we hypothesize that IHC induces specific alterations in the gut microbiome and microbial-derived metabolites, and these changes causally promote atherosclerosis. Indeed, we have obtained strong candidate microbial families and metabolites that can affect vascular integrity under IHC. For example, we have found that a) IHC accelerates the formation of atherosclerosis in ApoE-/- mice; b) IHC changes the gut microbiome ecology of families such as Verrucomicrobiaceae, Ruminococcaceae and Erysipelotrichaceae; and c) IHC alters microbial-derived metabolites (such as bile salts (BAs)). In the current application, we focus on these microbiota and metabolite candidates to investigate their role in atherosclerosis. First, we will isolate specific gut microbial strains that were altered by IHC treatment and determine the role of these specific microbial strain(s) in the development of cardiovascular disease in vivo using germ-free ApoE-/- mice that were currently created and established in our laboratory. Second, we will delineate the role of the major bile acid receptors (i.e., FXR and TGR5) in mediating the effect of candidate bile acids in IHC-induced cardiovascular disease in vivo using ApoE-/-/FXR-/- and ApoE-/-/TGR5-/- double knockout mice strains as well as the mice strains carrying cell specific conditional deletion of FXR and TGR5 on ApoE-/- background. And third, we will dissect the mechanisms underlying the role of specific IHC-altered bile acids (i.e., TβMCA and UDCA) in IHC-induced macrophage foam cell formation in vitro using primary cell cultures that are derived from mice with ApoE-/- /FXR-/- and ApoE-/-/TGR5-/- double deletion. This project will delineate novel mechanisms regulating OSA- induced cardiovascular disease and provide potential novel targets and strategies to improve treatment or prevent disease.


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 = $641,243 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	National Center on Sleep Disorders Research	000	4	11/29/2024	NON-COMPETING CONTINUATION	$641,243
														Subtotal = $641,243

Issue Date FY: 2024 ( Subtotal = $706,199 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	National Center on Sleep Disorders Research	000	3	12/18/2023	NON-COMPETING CONTINUATION	$648,551
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	National Center on Sleep Disorders Research	001	3	6/8/2024	NON-COMPETING CONTINUATION	$57,648
														Subtotal = $706,199

Issue Date FY: 2023 ( Subtotal = $722,577 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	National Center on Sleep Disorders Research	000	2	12/16/2022	NON-COMPETING CONTINUATION	$650,320
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	National Center on Sleep Disorders Research	001	2	3/10/2023	NON-COMPETING CONTINUATION	$72,257
														Subtotal = $722,577

Issue Date FY: 2022 ( Subtotal = $726,129 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	National Center on Sleep Disorders Research	001	1	9/26/2022	NEW	$0
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	National Center on Sleep Disorders Research	000	1	12/24/2021	NEW	$726,129
														Subtotal = $726,129

Grand Total All Awards = $2,796,148

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Obstructive sleep apnea, the microbiome and cardiovascular disease

Award Number: R01HL157445

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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