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Hydrogel matrices to study the role of inflammation and biological sex on aortic valve fibrocalcification

Award Number: R01HL171197
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/05/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Hydrogel matrices to study the role of inflammation and biological sex on aortic valve fibrocalcification - ABSTRACT Thirteen percent of adults over 75 suffer from aortic valve stenosis (AVS), a progressive disease that leads to aberrant collagen deposition, leaflet stiffening, and eventual valve calcification at late stages. AVS is also sexually dimorphic with men having a two-fold higher risk for developing direct calcification, whereas women with equal disease severity tend to have more valvular fibrosis prior to calcification. The molecular mechanisms underlying sexual dimorphism in AVS progression remain poorly understood, but growing evidence suggests AVS is an inflammation-dependent disease. Sex is known to influence the magnitude of the immune response and function, so we propose to investigate the role of inflammation in sex-specific valve disease progression. We hypothesize that three major variables contribute to differences in valve calcification in male and female patients: (1) heightened myofibroblast activation in female valve cells when exposed to inflammatory cues, (2) elevated expression of bone mineralization inhibitors, such as osteopontin, in female valve cells, and (3) sex- specific differences in epigenetic machinery. To test these hypotheses, we will develop sex-specific in vitro models of fibro-calcification that are comparable to diseased valve tissue. We will then investigate the sex- specific role that macrophage and valvular interstitial cell (VIC) crosstalk has on AVS (Aim 1) and determine the role of epigenetics in sex-specific regulation of calcification regulators (Aim 2). Ultimately, we aim to identify sex- specific therapies targeted to VIC populations to slow or halt AVS disease progression (Aim 3).


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: 2026 ( Subtotal = $637,519 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80303	BOULDER	USA	Cardiovascular Diseases Research	000	3	3/25/2026	NON-COMPETING CONTINUATION	$637,519
														Subtotal = $637,519

Issue Date FY: 2025 ( Subtotal = $659,531 )
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	2	4/11/2025	NON-COMPETING CONTINUATION	$593,579
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	001	2	7/16/2025	NON-COMPETING CONTINUATION	$65,952
														Subtotal = $659,531

Issue Date FY: 2024 ( Subtotal = $675,614 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	1	7/5/2024	NEW	$675,614
														Subtotal = $675,614

Grand Total All Awards = $1,972,664

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Hydrogel matrices to study the role of inflammation and biological sex on aortic valve fibrocalcification

Award Number: R01HL171197

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/05/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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