Tuesday, July 1, 2025 7/1/2025

Managing Cardiac Toxicities of Cancer Therapy

Award Number: R35HL155651
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Managing Cardiac Toxicities of Cancer Therapy - Project Summary This R35 application proposes to capitalize on previous work produced by the PI over the past 11 years and to further serve as a strong foundation for interrogating the role of sterile cardiac inflammation (inflammasomes) in promoting the progression of heart failure caused by chemotherapy-induced cardiotoxicity and complicated with myocardial ischemia. The overarching goal of this program is to better understand how inflammasome formation/activation in the heart secondary to different stress signals perpetuates myocardial injury and also dissect the contributions of different cardiac cell types during this pathophysiologic process. 1) Previous studies from the PI’s lab have characterized the role of the inflammasome in mediating adverse cardiac remodeling following acute myocardial infarction in preclinical models. 2) Other studies from the PI’s lab also demonstrated that NLRP3 inflammasome inhibition reduced interstitial fibrosis and preserved systolic cardiac function in mice exposed to doxorubicin. Evidence from the literature also supports a pathophysiologic role of NLRP3 in mediating doxorubicin-induced cardiotoxicity. Moreover, studies from the PI’s lab and others have shown that endogenous production of hydrogen sulfide (H2S) is essential for survival during cellular stresses, including ischemia, and that administration of H2S donors further promotes survival. The orally-active H2S- donor SG1002 was shown in a recent Phase I clinical trial to be safe and tolerable in heart failure patients and also to increase blood H2S levels as well as circulating nitric oxide while attenuating BNP. We recently demonstrated that H2S treatment attenuates ischemic and inflammatory (NLRP3 inflammasome) injury following myocardial infarction. Accordingly, modulation of the inflammasome with H2S may represent an important mechanism to limit inflammatory cell death and mitigate cardiomyopathy. Preliminary data demonstrate that increases in cofilin-2 expression and its potential for phospohorylation and oxidation under oxidative stress rises during ischemic injury, which is attenuated with H2S donors. Thus, this proposal provides the opportunity to perform in-depth investigations on role of the cardiac inflammasome and structural proteins, such as cofilin2, in heart failure due to chemotoxicity and also when complicated with myocardial infarction, therefore extending our knowledge on the potential mechanism of cardiotoxicity and facilitating the design and development of novel preventive/therapeutic modalities in the emerging field of cardio-oncology.


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 = $698,624 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	5	11/20/2024	NON-COMPETING CONTINUATION	$698,624
														Subtotal = $698,624

Issue Date FY: 2024 ( Subtotal = $760,725 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	001	4	6/26/2024	NON-COMPETING CONTINUATION	$62,101
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	4	11/23/2023	NON-COMPETING CONTINUATION	$698,624
														Subtotal = $760,725

Issue Date FY: 2023 ( Subtotal = $776,250 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	001	3	3/3/2023	NON-COMPETING CONTINUATION	$77,626
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	3	11/30/2022	NON-COMPETING CONTINUATION	$698,624
														Subtotal = $776,250

Issue Date FY: 2022 ( Subtotal = $776,250 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	2	12/8/2021	NON-COMPETING CONTINUATION	$698,623
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	001	2	6/13/2022	NON-COMPETING CONTINUATION	$77,627
														Subtotal = $776,250

Issue Date FY: 2021 ( Subtotal = $776,250 )
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	001	1	1/7/2021	NEW	$0
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cardiovascular Diseases Research	000	1	12/28/2020	NEW	$776,250
														Subtotal = $776,250

Grand Total All Awards = $3,788,099

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Managing Cardiac Toxicities of Cancer Therapy

Award Number: R35HL155651

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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