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Molecular Regulation of Functional Maturation in Human Direct Cardiac Reprogramming

Award Number: R01HL153220
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/25/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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Molecular Regulation of Functional Maturation in Human Direct Cardiac Reprogramming - PROJECT SUMMARY Heart disease remains a leading cause of mortality due to the heart's limited regenerative capacity. Direct cardiac reprogramming, which converts fibroblasts into induced cardiomyocytes (iCMs), offers a promising strategy for in situ regeneration while minimizing tumorigenesis risk. Despite significant progress in mouse models, the functional maturation of human iCMs remains inadequate, highlighting the need for deeper mechanistic insights. Building on previous identification of TBX20 as a key enhancer of cardiomyocyte maturation, we have discovered SMYD1 as a major downstream target that mediates TBX20's function. Our preliminary data demonstrate that SMYD1 plays a critical role in promoting iCM maturation. Overexpression of SMYD1 significantly enhanced reprogramming efficiency and improved the quality of iCMs. Among the SMYD family members, SMYD1 is uniquely expressed and functional in iCMs. Mechanistically, SMYD1 led to a global activation of genes associated with oxidative phosphorylation, mitochondrial function, and ion channel regulation. Furthermore, SMYD1 interacts with MEF2C and GATA4, stabilizing their protein expression through a mechanism dependent on its protein-protein interaction MYND domain. SMYD1's histone methyltransferase activity also contributes to iCM maturation by specifically methylating histone H3 at lysine 4 (H3K4). These findings provide strong scientific rationale for our central hypothesis that maturation of cardiac reprogramming requires coordinated transcriptional and epigenetic reconstitution mediated by SMYD1. To further test this hypothesis, we propose two specific aims: (1) to define the capability of SMYD1 in enhancing the functional maturation of iCMs, and (2) to elucidate how SMYD1 regulates iCM maturation at different regulatory levels. In Aim 1, we will assess SMYD1's impact on cardiac maturation mimicking ventricular identity; we will define the role of SMYD1 in metabolism maturation of human iCMs; we will also determine the functional improvement of SMYD1-induced iCMs in vivo. In Aim 2, we will determine the impact of SMYD1's interactions on gene regulation, investigate the novel function of SMYD1 in regulating protein stabilization, and dissect the epigenetic regulation of SMYD1 in iCM maturation. The overall objective of this proposal is to define the role of SMYD1 in promoting the functional maturation of iCMs and to uncover molecular mechanisms underlying its regulatory functions. Results from this proposal will advance our understanding of key regulators involved in the maturation stage of cardiac reprogramming and enhance the potential of functional iCMs for heart repair and regeneration.


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 = $487,421 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	5	6/16/2026	COMPETING CONTINUATION	$487,421
2026	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	6/3/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $487,421

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	8/6/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $371,250 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	7/12/2023	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2022 ( Subtotal = $371,250 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	3	7/8/2022	NON-COMPETING CONTINUATION	$371,250
2022	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	2	2/28/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $371,250

Issue Date FY: 2021 ( Subtotal = $371,250 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	2	7/22/2021	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2020 ( Subtotal = $371,250 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	1	8/21/2020	NEW	$371,250
														Subtotal = $371,250

Grand Total All Awards = $1,972,421

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Molecular Regulation of Functional Maturation in Human Direct Cardiac Reprogramming

Award Number: R01HL153220

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/25/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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