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Type I Interferon Responses in the Pathobiology of Anthracycline-induced Cardiotoxicity

Award Number: R01HL148153
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/05/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Type I Interferon Responses in the Pathobiology of Anthracycline-induced Cardiotoxicity - Anthracycline chemotherapeutics, such as doxorubicin (Doxo), are among the most effective and widely used antineoplastic drugs, yet their clinical application is limited by the damaging cardiac side effects that occur in many patients. Anthracycline-induced cardiotoxicity (AIC) can manifest acutely during cancer treatment, but can also cause life threatening cardiomyopathy and heart failure that develops years after the cessation of chemotherapy. Despite significant effort, the underlying mechanisms responsible for AIC are not fully defined, and it remains impossible to predict which patients will experience cardiotoxicity. Thus, there is an urgent need to advance mechanistic understanding in order to discover novel treatments and/or predictive biomarkers for this devastating condition. The overall objective of this proposal is to comprehensively define how type I interferon (IFNab) signaling, a pleiotropic innate immune pathway, potentiates the cardiotoxic effects of Doxo chemotherapy. The central hypothesis is that Doxo-induced cardiac DNA damage triggers the Stimulator of Interferon Genes (STING)-dependent production of IFNab, in turn driving a self-propagating cycle of mitochondrial dysfunction, reactive oxygen species (ROS) production, and cardiomyocyte death that contributes to cardiac remodeling and failure. In support of this hypothesis, ongoing studies have revealed that Doxo robustly engages STING to upregulate IFNab responses in cardiac cells and tissue. Strikingly, both male and female mice lacking STING or IFNab signaling are protected from Doxo-induced cardiac mitochondrial damage, myocardial remodeling, and left ventricle dysfunction. Conversely, treating melanoma-bearing mice with adjuvant IFNa in addition to Doxo results in enhanced cardiac fibrosis and contractility defects relative to tumor-bearing mice receiving Doxo alone. To gain additional insight into what appears to be an unappreciated yet fundamental driver of AIC, three related, but independent, aims are proposed. Aim 1 will employ single-cell approaches, a novel IFNab reporter mouse, and conditional knockout lines to define the kinetics of IFNab production in the heart and determine that STING-IFNab signaling in cardiac myeloid and myocyte populations contributes to AIC. Aim 2 will test the hypothesis that STING-IFNab signaling amplifies the cardiotoxicity of anthracyclines by potentiating mitochondrial dysfunction, iron overload, and oxidative stress. Finally, Aim 3 will establish that the IFNab-mediated upregulation of Z-DNA binding protein 1 (ZBP1) enhances sensing of cardiac DNA damage and promotes cardiac necroptosis to sustain inflammatory responses during and after Doxo chemotherapy. This proposal is innovative because it expands the current paradigms of AIC and defines the IFNab-mitochondrial nexus as a fundamental pathway contributing to myocardial damage. In addition, this research will contribute significant new information on how cardiac innate immune responses potentiate heart failure. In the long term, this work may positively impact human health by establishing IFNab as a predictive biomarker for cardiotoxicity and/or revealing novel therapeutic approaches to combat cancer therapy-related cardiac dysfunction.


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 = $0 )
2025	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cardiovascular Diseases Research	000	6	8/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $433,650 )
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cardiovascular Diseases Research	004	6	7/31/2024	NON-COMPETING CONTINUATION	$433,650
2024	2023	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Cardiovascular Diseases Research	000	4	1/11/2024	NON-COMPETING CONTINUATION	-$370,136
2024	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cardiovascular Diseases Research	003	5	5/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$304,893
2024	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cardiovascular Diseases Research	001	5	1/12/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$370,136
2024	2022	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Cardiovascular Diseases Research	002	3	5/9/2024	NON-COMPETING CONTINUATION	-$304,893
														Subtotal = $433,650

Issue Date FY: 2023 ( Subtotal = $370,136 )
2023	2023	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Cardiovascular Diseases Research	000	4	7/20/2023	NON-COMPETING CONTINUATION	$370,136
														Subtotal = $370,136

Issue Date FY: 2022 ( Subtotal = $370,547 )
2022	2022	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Cardiovascular Diseases Research	001	3	7/25/2022	NON-COMPETING CONTINUATION	$370,547
2022	2021	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Cardiovascular Diseases Research	000	2	11/11/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $370,547

Issue Date FY: 2021 ( Subtotal = $370,937 )
2021	2021	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Cardiovascular Diseases Research	000	2	7/27/2021	NON-COMPETING CONTINUATION	$370,937
														Subtotal = $370,937

Issue Date FY: 2020 ( Subtotal = $371,015 )
2020	2020	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Cardiovascular Diseases Research	000	1	8/5/2020	NEW	$371,015
														Subtotal = $371,015

Grand Total All Awards = $1,916,285

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Type I Interferon Responses in the Pathobiology of Anthracycline-induced Cardiotoxicity

Award Number: R01HL148153

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/05/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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