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Sex-Specific Risk of Metabolic and Cardiovascular Disease

Award Number: R01HL144846
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Sex-Specific Risk of Metabolic and Cardiovascular Disease - Men are at higher risk of coronary heart disease (CHD) than age- and BMI-matched women, especially early in life when androgens are high. However, androgens are needed for health in men, particularly in muscle where they promote glucose metabolism and fatty acid utilization. Gap: we don’t know the mechanisms for the disconnect between the protective functions of androgens and the higher risk of CHD in men. Additionally, although men and women share risk factors for CHD (hypertension, high LDL cholesterol and others), there are likely also sex-specific risk factors for the development of diabetes, fatty liver, and cardiovascular disease in both males and females. We don’t know the therapeutic significance of targeting these sex-specific pathways. In the last funding cycle of this project, our group helped define mechanisms for numerous species differences in the risk of metabolic and CHD with obesity. In humans and rodents, endogenous estrogens and androgens have beneficial effects on glucose metabolism. The increased risk of CHD in men is unique to humans. One key species difference is that humans express cholesteryl ester transfer protein (CETP), which mice naturally lack. Using mice transgenic for CETP we “humanized” this pathway and discovered that CETP transduces unique estrogenic pathways in the liver of females that are beneficial. We discovered that CETP also transduces unique effects of androgens in liver of the males, but that these are largely harmful for triglyceride and cholesterol metabolism; thus “humanizing” these aspects of sex-specific CVD risk. Our overarching hypothesis is that hepatic CETP expression drives sex-specific risk of dyslipidemia and CHD by creating gain-of-function androgen signaling and estrogen signaling in in the liver. We propose 3 AIMS to reduce the harmful lipid effects of androgens in males and preserve the beneficial glucose effects. Additionally, we will identify sex-specific risk factors in both males and females and help translate them to therapeutic targets. In AIM1 we will knock-down hepatic androgen receptor, or over-express hepatic CETP, to define if the CETP- androgen interaction that causes dyslipidemia is a direct effect of androgens and CETP in the liver. We will use metabolic tracers to simultaneously define glucose and fatty acid metabolism in both liver and muscle. We found that CETP alters androgen-regulation of ~3900 liver mRNAs, including gain-of-function for cholesterol and triglyceride metabolism. In AIM2 we will target two key factors that are uniquely up-regulated by androgens when CETP is present, LXR and ChREBP. We expect to preserve androgen benefits on muscle glucose and fatty acid metabolism but block the CETP-androgen axis with regard to dyslipidemia and CHD risk. In AIM3 we will take approaches to reduce the key translational barriers in the mouse with regard to lipid metabolism: 1) the absence of CETP; 2) increased metabolic rate; and 3) different bile acid composition. We will use approaches for each to make them more human-like, then with this model the demonstrate proof-of-principle therapeutic value of a liver-targeted estrogen-glucagon receptor co-agonist in both males and females.


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 = $733,978 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	6	3/28/2025	NON-COMPETING CONTINUATION	$660,581
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	001	6	7/21/2025	NON-COMPETING CONTINUATION	$73,397
														Subtotal = $733,978

Issue Date FY: 2024 ( Subtotal = $725,712 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	002	5	5/31/2024	COMPETING CONTINUATION	$75,192
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	001	5	3/12/2024	COMPETING CONTINUATION	$676,286
2024	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	4	1/19/2024	NON-COMPETING CONTINUATION	-$25,766
														Subtotal = $725,712

Issue Date FY: 2022 ( Subtotal = $482,584 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	4	5/9/2022	NON-COMPETING CONTINUATION	$482,584
														Subtotal = $482,584

Issue Date FY: 2021 ( Subtotal = $482,579 )
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	3	5/18/2021	NON-COMPETING CONTINUATION	$482,579
														Subtotal = $482,579

Issue Date FY: 2020 ( Subtotal = $487,084 )
2020	2020	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	2	5/28/2020	NON-COMPETING CONTINUATION	$487,084
														Subtotal = $487,084

Issue Date FY: 2019 ( Subtotal = $520,958 )
2019	2019	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	1	6/6/2019	NEW	$520,958
														Subtotal = $520,958

Grand Total All Awards = $3,432,895

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Sex-Specific Risk of Metabolic and Cardiovascular Disease

Award Number: R01HL144846

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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