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Altering Cardiac Cell Fate for Heart Repair

Award Number: R35HL155656
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/13/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Altering Cardiac Cell Fate for Heart Repair - Abstract Direct cardiac reprogramming holds great promise as a novel therapy for heart failure, a common and morbid disease that is usually caused by irreversible loss of massive functional cardiomyocytes. By leveraging the knowledge in developmental and stem cell biology gained during my PhD and postdoc training, in 2012 I demonstrated that in a murine acute myocardial infarction model, delivery of three transcription factors, Gata4, Mef2c and Tbx5 (GMT) converted cardiac fibroblasts (CFs) into functional induced cardiomyocytes (iCMs) that integrated electrically and mechanically with surrounding myocardium, resulting in functional improvement and scar size reduction. These findings suggest that iCM reprogramming is an effective means of regenerating heart tissue in vivo for human patients with heart disease. However, because relatively little was known about the factors that allow CFs to be reprogrammed, the applicability of cardiac reprogramming was limited to the context in which it had been attempted at that time. Since my independence, my own laboratory has established robust murine and human iCM reprogramming systems. By using these systems, we obtained novel insights into the transcriptional, post-transcriptional and epigenetic regulation of both murine iCM (supported by R01HL128331 as ESI) and human iCM reprogramming (supported by R01HL144551), and concomitantly improved the quality and yield of iCMs. This R35 EIA application is an extension to these two currently funded NHLBI R01 grants to further unravel the molecular mechanisms underlying iCM conversion, to test in vivo iCM reprogramming in non- acutely injured hearts and to exploit the latest single cell multi-omics and mathematical modeling for optimized and individualized reprogramming. Successful completion of this proposal will help to move direct cardiac reprogramming closer to its clinical application, provide new insights into molecular mechanisms underlying cardiac cell fate determination, and open new opportunities for the field to leverage the models and platforms we will develop here to study other cardiovascular physiological and pathological processes.


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 = $881,659 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	6	2/25/2026	NON-COMPETING CONTINUATION	$881,659
														Subtotal = $881,659

Issue Date FY: 2025 ( Subtotal = $928,062 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	5	8/4/2025	NON-COMPETING CONTINUATION	$92,805
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	5	11/13/2024	NON-COMPETING CONTINUATION	$835,257
														Subtotal = $928,062

Issue Date FY: 2024 ( Subtotal = $909,501 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	4	11/6/2023	NON-COMPETING CONTINUATION	$835,257
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	002	4	6/13/2024	NON-COMPETING CONTINUATION	$74,244
2024	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	3	10/17/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $909,501

Issue Date FY: 2023 ( Subtotal = $928,062 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	3	11/15/2022	NON-COMPETING CONTINUATION	$835,257
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	3	3/3/2023	NON-COMPETING CONTINUATION	$92,805
														Subtotal = $928,062

Issue Date FY: 2022 ( Subtotal = $928,062 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	2	6/18/2022	NON-COMPETING CONTINUATION	$92,806
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	2	11/5/2021	NON-COMPETING CONTINUATION	$835,256
														Subtotal = $928,062

Issue Date FY: 2021 ( Subtotal = $928,062 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	1	1/13/2021	NEW	$928,062
														Subtotal = $928,062

Grand Total All Awards = $5,503,408

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Altering Cardiac Cell Fate for Heart Repair

Award Number: R35HL155656

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/13/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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