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Epigenetic reprogramming of cardiac myofibroblasts for cardiac repair

Award Number: R01HL169964
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Epigenetic reprogramming of cardiac myofibroblasts for cardiac repair - PROJECT SUMMARY Heart failure is associated with activation of cardiac fibroblasts (Fib), which promotes cardiac fibrosis and pathological cardiac remodeling. Employing single-cell RNA-sequencing (scRNA-seq) in adult mouse hearts, we discovered that Enhancer of Zeste homolog 2 (EZH2), the major enzyme known to catalyze the transcriptional repression mark H3K27me3, is highly expressed in a specific POSTN+ Fib subpopulation (myofibroblasts, MFib). Of note, little is known about the functional role of EZH2 in regulating cardiac MFib, which is a critical knowledge gap given their epigenetic variability and pathological role. We demonstrate that although these MFib express GATA4, an early cardiac transcription factor, they fail to express the cardiovascular progenitor (CPC) gene programs, such as NKX2.5. Importantly, deletion of EZH2 inhibited MFib proliferation and switched on cardiovascular progenitor cell (CPC) gene programs. Moreover, deletion of EZH2 increased the pro-angiogenic paracrine effects of MFib and improved cardiac function post myocardial infarction (MI) These beneficial effects on cardiac function were lost in mice administered a novel rAAV-FLEX-DTA vector, which ablates MFib lacking EZH2, confirming the important functional role of this cell population. These findings suggest that EZH2 is a restraint on the transition of MFib to beneficial phenotypes and that inhibition of EZH2 provides a unique therapeutic approach to diminishing MFib proliferation while activating repair mechanisms. The overall goal of this project is to test the central hypothesis that EZH2 inhibition in myofibroblasts can transform the cell fate from pro-fibrotic myofibroblasts into pro-angiogenic CPC, thus attenuating fibrosis, improving cardiac angiogenesis, and boosting cardiac repair in the ischemic myocardium. This proposed project is innovative because it will generate unique mechanistic insights from novel approaches to cardiac regeneration by transforming cardiac myofibroblasts from a proliferative and pro-fibrotic phenotype to a pro-angiogenic and pro- regenerative phenotype. Our focus on EZH2-mediated chromatin remodeling in epigenetic repression of GATA4-mediated CPC program is translationally significant, as EZH2 inhibitors are available clinically and have recently been approved for the treatment of follicular lymphoma. Our preliminary findings highlight the potential for this pathway to be the focus of novel strategies for mitigating cardiac fibrosis and promoting cardiac angiogenesis after ischemic injury.


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 = $509,007 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	3	6/9/2025	NON-COMPETING CONTINUATION	$509,007
														Subtotal = $509,007

Issue Date FY: 2024 ( Subtotal = $498,828 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	2	6/28/2024	NON-COMPETING CONTINUATION	$498,828
														Subtotal = $498,828

Issue Date FY: 2023 ( Subtotal = $509,007 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	1	6/6/2023	NEW	$509,007
														Subtotal = $509,007

Grand Total All Awards = $1,516,842

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Epigenetic reprogramming of cardiac myofibroblasts for cardiac repair

Award Number: R01HL169964

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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