Monday, February 6, 2023 2/6/2023

Impact of sex and sex hormones on mechanobiological mechanisms of pulmonary hypertension secondary to left heart failure

Award Number: R01HL147590
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT ABSTRACT The role of sex in cardiovascular disease (CVD) remains a critically understudied area in determining the etiology, pathology, and effective treatments. Whereas men experience a gradual increase in CVD risk over the lifespan, premenopausal women are protected from CVD-related pathologies. However, post-menopause the onset of CVD in women increases dramatically. Endothelial cell dysfunction may contribute to these sex and sex hormone-dependent differences in CVD risk. Here we seek to investigate the impact of sex and sex hormone- dependent differences in progression of the CVD disease pulmonary hypertension secondary to left heart failure (PH-LHF). Aim 1: Investigate the role of sex and sex hormones in pulmonary endothelial cell mechanotransduction and disease progression. First, we will test the hypothesis that female sex alters endothelial cell signaling in response to mechanical shear stress. Human male and female pulmonary artery, vein, and microvascular endothelial cells will be exposed to physiologic, high, and low levels of shear stress (s) to measure the effect of sex independent of sex hormones. Second, to investigate the role of sex coupled with female sex hormones, both male and female cells will be dosed with sex hormones at physiologic or pathologic s. These in vitro results will be confirmed as drivers of collagen over-production and chronic vasoconstriction in vivo using the established mouse model of PH-LHF. Aim 2: Determine the role of sex and sex hormones in the progression of PH-LHF with a coupled pulmonary hemodynamics and endothelial cell kinetics model of PH-LHF. Informed by the existing literature, we will develop a chemical kinetics model of the endothelial response to altered s, sex, and sex hormones. Using idealized human structural and hemodynamic data we will develop a computational model of the pulmonary vasculature integrated with the chemical kinetics equations for key signaling factors. Parameter values and dependencies will be validated against the in vitro data collected in Aim 1. To confirm predictive capability, the model will be calibrated to the in vivo mouse model of PH-LHF and used to estimated pulmonary artery and vein remodeling.


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: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cardiovascular Diseases Research	000	4	10/13/2022	SUPPLEMENT FOR EXPANSION	$0


Issue Date FY: 2022 ( Subtotal = $671,795 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Lung Diseases Research	003	4	5/27/2022	NON-COMPETING CONTINUATION	$576,890
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cardiovascular Diseases Research	004	4	8/17/2022	SUPPLEMENT FOR EXPANSION	$94,905
2022	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Lung Diseases Research	001	3	3/21/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$688,968
2022	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Lung Diseases Research	002	3	5/26/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Lung Diseases Research	000	2	3/18/2022	NON-COMPETING CONTINUATION	-$688,968


Issue Date FY: 2021 ( Subtotal = $688,968 )
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Lung Diseases Research	001	2	5/31/2021	NON-COMPETING CONTINUATION	$688,968
2021	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Lung Diseases Research	000	1	4/2/2021	NEW	$0


Issue Date FY: 2020 ( Subtotal = $676,638 )
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Lung Diseases Research	000	1	5/21/2020	NEW	$676,638


Grand Total All Awards = $2,037,401

Sum of Action Amount is $2,037,401;

Grand Total = $2,037,401

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Impact of sex and sex hormones on mechanobiological mechanisms of pulmonary hypertension secondary to left heart failure

Award Number: R01HL147590

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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