Monday, February 10, 2025 2/10/2025

Understanding the molecular mechanism of cardiomyocyte dedifferentiation and proliferation during regeneration

Award Number: R01HL156398
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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1 Heart disease is the leading cause of death and a significant health burden to society, in particular myocardial 2 infarctions are responsible for a large number of premature deaths world-wide. After a cardiac ischemic event, 3 damaged cells die via necrosis and apoptosis and is replaced by scar tissue. The presence of fibrotic scar tissue 4 diminishes cardiac function and overtime infarcted hearts undergo failure. Recent studies have shown that a 5 limited number of spared cardiomyocytes can dedifferentiate and proliferate in response to injury, but this 6 process fails to sufficiently replace lost cells. However, these studies offer new approaches to stimulate cardiac 7 repair. One clear obstacle is to understand the how mature mammalian cardiomyocytes are restricted from 8 proliferation in the adult hearts. Although the mammalian heart shows limited capacity in repair and regeneration, 9 the adult zebrafish heart is endowed with a robust regenerative response to a variety of injury models. The adult 10 zebrafish heart can efficiently replicate cardiomyocytes, and can stimulate endocardium and coronary vessel 11 regeneration such that damage or lost tissue is completely replaced within weeks. The major goal of this proposal 12 is to understand how the zebrafish heart, specifically cardiomyocytes are activated in response to ventricular 13 injury to dedifferentiate and proliferate. Findings from these studies will provide important factors that are critical 14 for driving completion of cardiomyocyte cell cycle after injury. In preliminary studies, we performed transcriptome 15 profiling (RNA-seq) on ventricular resected hearts and identified a number of genes that are highly expressed 16 following injury. Our studies reveal that one of these genes, the forkhead transcription factor, foxm1 is 17 upregulated in cardiomyocytes that are within the injury border zone. Studies with foxm1 mutant zebrafish 18 showed cardiomyocyte cell cycling was diminished and failure to resolve scar tissue upon ventricular resection. 19 Transcriptome profiling foxm1 mutant hearts show a marked decrease in expression of cell cycle genes involved 20 in G2/M transition suggesting that Foxm1 may be a critical driver of cardiomyocyte cytokinesis. In addition, we 21 have identified candidate foxm1 target genes implicated to be involved in cardiomyocyte differentiation and 22 mitosis. We therefore propose to characterize the molecular control of cardiomyocyte dedifferentiation and 23 proliferation through extensive study of foxm1 and downstream target genes. The findings from these studies 24 will identify new molecular pathways and factors to that have the potential to stimulate repair and regeneration 25 after myocardial infarction to address a societal health burden.


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 = $485,564 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	4	1/10/2025	NON-COMPETING CONTINUATION	$485,564
														Subtotal = $485,564

Issue Date FY: 2024 ( Subtotal = $532,056 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	001	3	6/26/2024	NON-COMPETING CONTINUATION	$43,432
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	3	11/30/2023	NON-COMPETING CONTINUATION	$488,624
														Subtotal = $532,056

Issue Date FY: 2023 ( Subtotal = $547,171 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	2	12/12/2022	NON-COMPETING CONTINUATION	$492,455
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	001	2	3/6/2023	NON-COMPETING CONTINUATION	$54,716
														Subtotal = $547,171

Issue Date FY: 2022 ( Subtotal = $550,836 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	1	12/15/2021	NEW	$550,836
														Subtotal = $550,836

Grand Total All Awards = $2,115,627

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Understanding the molecular mechanism of cardiomyocyte dedifferentiation and proliferation during regeneration

Award Number: R01HL156398

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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