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Cell cycle proteins as key regulators of cardiac chemosensitivity

Award Number: R01HL151472
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/16/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Cell cycle proteins as key regulators of cardiac chemosensitivity - PROJECT SUMMARY Anthracycline-based chemotherapy, an effective treatment for many types of cancer, has long been associated with substantial cardiotoxicity. As one of the most commonly used anthracycline anticancer agent, doxorubicin (DOX) induces DNA damage and subsequent cardiomyocyte apoptosis, eventually resulting in cardiomyopathy and heart failure. Therefore, understanding the mechanisms of DOX-induced apoptosis is of paramount importance for cardioprotection. Our published work has identified cyclin-dependent kinase 2 (CDK2) as a critical mediator of anthracycline cardiotoxicity. Mechanistically, CDK2 augments forkhead box O1 (FOXO1)-dependent expression of Bim, a pro-apoptotic protein indispensable for DOX-induced cardiomyocyte apoptosis. Based on these findings, we hypothesize that cardiac CDK2 activity determines chemotherapy sensitivity (chemosensitivity) in the heart. CDK2 is best known for its classical role in cell cycle progression in proliferating cells, and its activity is tightly controlled by multiple proteins involved in cell cycle regulation. Since cardiomyocytes are postmitotic cells with minimal cell cycle activity, it remains to be determined how CDK2 activity is regulated in the cardiac settings. Interestingly, our preliminary results revealed that CDK2 was activated by CDK7, but inhibited by retinoblastoma-like 2 (RBL2) in cardiomyocytes. In this application, we propose to tackle the roles of these cell cycle proteins in cardiomyocyte apoptosis and cardiac chemosensitivity. This proposal has three Specific Aims: 1) Define the role of CDK7 in DOX-induced CDK2 activation and cardiomyocyte apoptosis; 2) Assess the feasibility of the CDK7-CDK2 axis as a new drug target for DOX cardiotoxicity; and 3) Determine how RBL2 regulates CDK2 activity and cardiac DOX sensitivity. Our approach is innovative because various state-of-the- art systems will be used, including immunocompetent mouse tumor allograft model and genetically engineered mouse models. The novel mechanisms established in this application will have great translational potential, and could lay the foundation for developing new cardioprotective strategies during cancer treatment.


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	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cardiovascular Diseases Research	000	4	5/22/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $475,174 )
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cardiovascular Diseases Research	001	4	6/19/2024	NON-COMPETING CONTINUATION	$38,791
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cardiovascular Diseases Research	000	4	1/24/2024	NON-COMPETING CONTINUATION	$436,383
														Subtotal = $475,174

Issue Date FY: 2023 ( Subtotal = $484,870 )
2023	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cardiovascular Diseases Research	000	3	1/24/2023	NON-COMPETING CONTINUATION	$484,870
														Subtotal = $484,870

Issue Date FY: 2022 ( Subtotal = $486,581 )
2022	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cardiovascular Diseases Research	001	2	6/8/2022	NON-COMPETING CONTINUATION	$48,659
2022	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cardiovascular Diseases Research	000	2	1/31/2022	NON-COMPETING CONTINUATION	$437,922
														Subtotal = $486,581

Issue Date FY: 2021 ( Subtotal = $496,410 )
2021	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cardiovascular Diseases Research	001	1	6/19/2021	NEW	$49,641
2021	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cardiovascular Diseases Research	000	1	2/16/2021	NEW	$446,769
														Subtotal = $496,410

Grand Total All Awards = $1,943,035

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Cell cycle proteins as key regulators of cardiac chemosensitivity

Award Number: R01HL151472

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/16/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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