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Origins of sex differences in the mechanisms of obesity-associated hypertension

Award Number: F31HL168963
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Origins of sex differences in the mechanisms of obesity-associated hypertension - PROJECT SUMMARY Obesity, which affects more than 42% of adults in the US, is the leading risk factor for hypertension. While premenopausal women are commonly viewed as protected from hypertension and cardiovascular disease, compelling evidence establishes that obesity abrogates the protective effects of female sex and predisposes women to vascular dysfunction and hypertension. Obesity-associated hypertension (OAH) involves the adipokine leptin in both males and females but through sex-specific mechanisms. We have shown that leptin elevates sympathetic activity in males whereas it stimulates aldosterone production and leads to the activation of the mineralocorticoid receptor (MR) signaling in endothelial cells in obese female mice. Clinical data indicate that obese women have disproportionately high aldosterone levels and are more responsive to MR blockers. However, a critical gap in knowledge is the source of these sex differences. Preliminary studies revealed that the absence of female sex hormone production with gonadectomy (GDX) had no additional effect on obese female mice. This novel data suggest that OAH remains leptin-dependent and aldosterone-mediated in the absence of female sex hormones and that female sex steroids play a limited role in the control of the development of OAH. Based on these findings, the central hypothesis of this proposal is that female sex chromosomes potentiate the adrenal leptin-CYP11B2-aldosterone axis in obesity. This hypothesis will be tested in 2 aims. Aim 1 will test the hypothesis that female sex chromosomes predispose to leptin-mediated aldosterone production and hypertension. We will investigate the mechanisms controlling leptin and aldosterone production, as well as BP regulation and vascular function, in leptin-infused GDX four-core genotype mice, a model dissociating gonadal phenotype from sex chromosomes. Aim 2, will test the hypothesis that human female adrenals are predisposed to exacerbated aldosterone production in response to leptin and obesity. We will take advantage of our access to freshly obtained human adrenals and human adrenocortical cells to determine whether female sex and obesity predispose adrenals to leptin-mediated aldosterone production and investigate the effects of obesity, sex and menopause on the signaling pathways regulating aldosterone production. From these studies, we expect to identify a role for sex chromosome complement in the sex specificity of the mechanisms of OAH as well as demonstrate that human female adrenals are more sensitive to leptin-mediated aldosterone production than that of males. The project will be conducted under the co-mentorship of Dr. Eric Belin de Chantemèle and Dr. Jennifer Sullivan, Vascular Biology Center and Department of Physiology at Augusta University, which has a rich history of successful pre- and post-doctoral training. The proposed project is for 3 years of funding with the proposed aims divided amongst the 3 years of funding, culminating with a dissertation defense at the end of the third year. We anticipate that findings from this novel proposal will unmask the origin and provide new information about the mechanism for sex differences in hypertension in obese women and lead to improved therapies.


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 = $43,076 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	3	2/21/2025	NON-COMPETING CONTINUATION	$42,512
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	3	6/23/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $43,076

Issue Date FY: 2024 ( Subtotal = $42,512 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	2	4/18/2024	NON-COMPETING CONTINUATION	$41,232
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	2	9/6/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $42,512

Issue Date FY: 2023 ( Subtotal = $41,232 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	1	3/10/2023	NEW	$0
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	1	3/10/2023	NEW	$41,232
														Subtotal = $41,232

Grand Total All Awards = $126,820

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Origins of sex differences in the mechanisms of obesity-associated hypertension

Award Number: F31HL168963

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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