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Investigating the role of CaV1.2 in aortic valve stenosis

Award Number: R01HL151190
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Investigating the role of CaV1.2 in aortic valve stenosis - Calcific aortic valve disease (CAVD) is a progressive life-threatening disorder characterized by dystrophic and/or osteogenic transformation of valve cells (VICs), both leading to calcification. There are no medical therapies to prevent or delay CAVD. Building on a recent meta-analysis of genome-wide association studies that unexpectedly identified CACNA1C, encoding the pore-forming α subunit of the voltage gated L-type calcium channel CaV1.2, as a candidate CAVD susceptibility gene, we present preliminary data suggesting that Ca2+ influx through CaV1.2 in VICs is causal for CAVD. This raises the tantalizing possibility that clinically used Ca2+ channel antagonists (CCBs) may be an effective therapy. Although CCBs are generally contraindicated in patients with severe CAVD, they would be reasonable therapies earlier in the disease process. We propose to test the overall hypotheses that: 1) increased Ca2+ influx through CaV1.2 in VICs leads to dystrophic and/or osteogenic transformation; and 2) reduction of Ca2+ influx through CaV1.2 with CCBs and/or by targeting Ca2+- dependent signaling molecules downstream of CaV1.2 in VICs delays CAVD progression. We developed novel mouse models and innovative VIC cultures to test those overall hypotheses with the following Aims: Aim 1: Can elevated Ca2+ influx through CaV1.2 activate VICs and/or increase expression of signaling pathway genes leading to dystrophic or osteogenic calcification in the AoV? Using porcine and murine VICs enhanced by transfection of informative cDNAs, we have developed means to dissect the Ca2+-dependent signaling pathways downstream of CaV1.2 that contribute to CAVD, and thereby to discover new potential therapeutic targets. We propose a multi-pronged approach to identify the critical downstream Ca2+-dependent signaling molecules and pathways leading to activation of dystrophic VICs and/or osteogenic transformation of VICs; Aim 2: Can inhibition of CaV1.2 signaling pathways in the aortic valve decrease the valve pathology? With novel mouse models that mimic the increased CaV1.2 expression and signaling in human CAVD, we propose to test if CCBs ameliorate valve lesions and reverse the disease process once calcification is initiated. We further propose to build upon our identification of novel candidate targets from Aim 1 to test if manipulating these targets similarly reduces or slows CAVD progression. Aim 3: Does excess Ca2+ influx through CaV1.2 contribute to CAVD in the context of hyperlipidemia? Hyperlipidemia is a prominent CAVD risk factor. In coronary artery disease, a related disorder, long ignored data point to a synergistic interaction between CaV1.2 and hyperlipidemia. We propose: to test with novel mouse models whether Ca2+ influx through CaV1.2 in VICs or macrophages accelerates AoV lesions in the context of hyperlipidemia and, as a corollary, whether CCBs are effective when the disease process is driven by hyperlipidemia, thereby determining whether targeting the CaV1.2 pathway is broadly applicable in patients.


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 = -$406 )
2026	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cardiovascular Diseases Research	000	4	12/4/2025	NON-COMPETING CONTINUATION	-$406
														Subtotal = -$406

Issue Date FY: 2023 ( Subtotal = $872,702 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	001	4	4/14/2023	NON-COMPETING CONTINUATION	$793,204
2023	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	000	3	4/11/2023	NON-COMPETING CONTINUATION	$79,498
														Subtotal = $872,702

Issue Date FY: 2022 ( Subtotal = $715,449 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	000	3	4/19/2022	NON-COMPETING CONTINUATION	$715,449
														Subtotal = $715,449

Issue Date FY: 2021 ( Subtotal = $796,675 )
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	000	2	6/7/2021	NON-COMPETING CONTINUATION	$796,675
														Subtotal = $796,675

Issue Date FY: 2020 ( Subtotal = $798,364 )
2020	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	000	1	3/24/2020	NEW	$798,364
														Subtotal = $798,364

Grand Total All Awards = $3,182,784

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Investigating the role of CaV1.2 in aortic valve stenosis

Award Number: R01HL151190

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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