Wednesday, October 1, 2025 10/1/2025

Leptin and intermittent hypoxia interactions in the carotid bodies: mechanisms and consequences

Award Number: R01HL133100
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Leptin and intermittent hypoxia interactions in the carotid bodies: mechanisms and consequences - Obstructive sleep apnea (OSA) is recurrent closure of upper airway during sleep, which results in intermittent hypoxia (IH). OSA is the most common type of sleep disordered breathing (SDB), which is particularly prevalent in obesity affecting more than 50% individuals with BMI ≥ 30 kg/m2. OSA is a leading cause of hypertension with IH playing a major role. IH activates the sympathetic nervous system (SNS) inducing hypertension in humans and animal models. IH-induced activation of SNS originates in the carotid body (CB), a peripheral sensor of hypoxia, which provides key afferent input to medullary network that regulates SNS activity. Obesity also activates SNS and causes hypertension. CB plays a role in obesity-induced hypertension. Interactions between IH and obesity in CB, which are highly translationally relevant in SDB, have not been explored. This project will examine novel molecular targets in the CB differentially regulated by IH and obesity to optimize treatment of cardiovascular complications of OSA. During the previous funding periods of this award we identified a pathway by which obesity increases CB and carotid sinus nerve (CSN) activity leading to hypertension. Specifically, we have shown that obesity-induced hypertension is a consequence of leptin binding to the leptin receptor LEPRb on hypoxia-sensing tyrosine hydroxylase (TH) positive CB type I cells, which leads to up-regulation of the transient receptor potential melastatin-subfamily member 7 (TRPM7). Our Preliminary Data demonstrate that IH increases expression of TRPM7 in CB and CSN activity and that pharmacological and genetic blockade of CB TRPM7 abolishes IH-induced hypertension. We have shown that both leptin and IH increase CB TRPM7 gene expression via epigenetic modifications including DNA demethylation of Trpm7 gene promoter. We identified three differentially methylated regions (DMRs) in the Trpm7 promoter, which can be demethylated by 5-aza- deoxycytidine. We demonstrated that DMR region 1 (R1) is selectively demethylated by obesity via the leptin- LEPRb mechanism, while the DMR region 2 (R2) and DMR region 3 (R3) are demethylated by IH. Furthermore, we provide preliminary data that targeted methylation of these regions in vivo greatly decreases Trpm7 gene expression in CB and decreases CSN activity and blood pressure. Our overarching hypothesis is that obesity and IH interact to induce epigenetic up-regulation of Trpm7 gene expression in CB and increase CSN and SNS activity leading to hypertension. We will use our mouse models of DIO and IH, wildtype and transgenic mouse strains to address this hypothesis in four aims. Specific Aims 1 and 2 will examine how IH and obesity interact on the CB TRPM7 to induce hypertension (Aim 1) and CSN/SNS activity (Aim 2) using genetic and pharmacological blockade of LEPRb and TRPM7 in CB. Specific Aims 3 and 4 will examine how IH and obesity affect methylation of the Trpm7 promoter in CB to induce hypertension (Aim 3) and CSN/SNS activity (Aim 4) using methylated oligonucleotides complementary to the DMRs R1, R2, and R3. Our proposal will contribute to pharmacotherapy of obesity and OSA and open new horizons for translational use of epigenetics.


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 = $743,127 )
2025	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center on Sleep Disorders Research	002	9	9/10/2025	COMPETING CONTINUATION	$743,127
2025	2024	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Lung Diseases Research	000	8	7/3/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center on Sleep Disorders Research	001	8	9/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $743,127

Issue Date FY: 2024 ( Subtotal = $777,366 )
2024	2024	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center on Sleep Disorders Research	002	8	6/25/2024	NON-COMPETING CONTINUATION	$46,733
2024	2024	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Lung Diseases Research	001	8	4/22/2024	SUPPLEMENT FOR EXPANSION	$204,887
2024	2024	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Lung Diseases Research	003	8	8/9/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center on Sleep Disorders Research	000	8	3/29/2024	NON-COMPETING CONTINUATION	$525,746
														Subtotal = $777,366

Issue Date FY: 2023 ( Subtotal = $634,633 )
2023	2023	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center on Sleep Disorders Research	002	7	7/17/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2023	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center on Sleep Disorders Research	004	7	8/7/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$611,313
2023	2023	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center on Sleep Disorders Research	001	7	6/20/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$634,633
2023	2022	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	003	6	8/7/2023	NON-COMPETING CONTINUATION	-$611,313
2023	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	000	6	6/19/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $634,633

Issue Date FY: 2022 ( Subtotal = $737,117 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	000	6	3/31/2022	NON-COMPETING CONTINUATION	$663,403
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	001	6	6/14/2022	NON-COMPETING CONTINUATION	$73,714
														Subtotal = $737,117

Issue Date FY: 2021 ( Subtotal = $745,529 )
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	003	5	8/5/2021	COMPETING CONTINUATION	$0
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	000	5	4/2/2021	COMPETING CONTINUATION	$745,529
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	002	5	7/22/2021	COMPETING CONTINUATION	$392
2021	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	001	4	7/22/2021	NON-COMPETING CONTINUATION	-$392
														Subtotal = $745,529

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	000	4	4/2/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $684,225 )
2019	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	000	4	3/25/2019	NON-COMPETING CONTINUATION	$684,225
														Subtotal = $684,225

Issue Date FY: 2018 ( Subtotal = $684,225 )
2018	2018	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	000	3	3/3/2018	NON-COMPETING CONTINUATION	$670,540
2018	2018	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	001	3	6/9/2018	NON-COMPETING CONTINUATION	$13,685
														Subtotal = $684,225

Issue Date FY: 2017 ( Subtotal = $684,225 )
2017	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	National Center on Sleep Disorders Research	000	2	2/28/2017	NON-COMPETING CONTINUATION	$684,225
														Subtotal = $684,225

Issue Date FY: 2016 ( Subtotal = $684,225 )
2016	2016	JOHNS HOPKINS UNIVERSITY	1101 E 33RD STREET, STE-C-210	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	1	6/10/2016	NEW	$684,225
														Subtotal = $684,225

Grand Total All Awards = $6,374,672

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Leptin and intermittent hypoxia interactions in the carotid bodies: mechanisms and consequences

Award Number: R01HL133100

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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