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Metabolic Control of Epigenetic Reprogramming in Neovascularization

Award Number: F30HL167457
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 05/17/2025
AWARD TERMINATION DATE: 09/05/2026

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Metabolic Control of Epigenetic Reprogramming in Neovascularization - Project Summary The ability to restore the microvasculature and improve perfusion, by expanding the population of endothelial cells in vivo, would be a major advancement in cardiovascular medicine and create a novel therapeutic approach to cardiovascular disease. The proposed studies, aimed at identifying the role of O-GlcNAcylation in transdifferentiation and epigenetic plasticity, may reveal a novel mechanism of neovascularization and uncover new avenues for therapeutic angiogenesis and vasculogenesis (Carmeliet, 2005, Isner 1999). Activation of inflammatory signaling pathways is required to drive fibroblasts to undergo angiogenic transdifferentiation and become endothelial cells in vitro (Sayed, 2015). This process requires cell autonomous innate immune signaling, which triggers global changes in expression and activity of epigenetic modifiers (Lee, 2012). The term “transflammation” describes the process by which innate immune signaling promotes epigenetic plasticity and phenotypic fluidity. Recently, it has been shown that a glycolytic shift contributes to transdifferentiation by increased nuclear acetyl-CoA for histone acetylation (Lai, 2019). Although this glycolytic switch links metabolism to epigenetic modelling, the contribution of other metabolites to epigenetic plasticity in neovascularization remains unexplored. Preliminary data indicate that O-GlcNAcylation, and nutrient driven post-translational modification (PTM), is significantly elevated in angiogenic transdifferentiation and neovascularization following hindlimb ischemia. This observation raises the exciting possibility that O-GlcNAcylation links cell fate plasticity to metabolism in vascular transdifferentiation, and that targeting this PTM may be a new therapeutic avenue in regenerative medicine. The overarching hypothesis is that O-GlcNAcylation enhances neovascularization in recovery from ischemic injury by facilitating cell fate plasticity, and that perturbations to O-GlcNAcylation through genetic and pharmacologic manipulation will attenuate transdifferentiation and diminish neovascularization. The immediate goal will be to determine if O-GlcNAcylation is required for angiogenic transdifferentiation and to identify targets of O-GlcNAcylation contributing to epigenetic plasticity and cell fate fluidity in vascular transdifferentiation and neovascularization. The proposed studies on O-GlcNAcylation in transdifferentiation will identify an epigenetic mechanism for cellular plasticity and a novel therapeutic target to enhance endogenous neovascularization for treatment of cardiovascular disease. The long term goal is to evaluate the therapeutic efficacy of targeting O-GlcNAcylation to enhance vascular recovery in non-ischemic and ischemic models of cardiovascular disease, such as heart failure and myocardial infarction. Aim 1: Determine the role of O-GlcNAcylation in transdifferentiation and DNA accessibility in vitro. Aim 2: Determine the role of O-GlcNAcylation in transdifferentiation and neovascularization in vivo.


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 = -$30,121 )
2026	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cardiovascular Diseases Research	000	3	9/4/2026	TERMINATION	-$30,121
														Subtotal = -$30,121

Issue Date FY: 2025 ( Subtotal = $41,252 )
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cardiovascular Diseases Research	001	3	7/28/2025	NON-COMPETING CONTINUATION	$564
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cardiovascular Diseases Research	000	3	2/14/2025	NON-COMPETING CONTINUATION	$40,688
														Subtotal = $41,252

Issue Date FY: 2024 ( Subtotal = $40,688 )
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cardiovascular Diseases Research	001	2	7/19/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cardiovascular Diseases Research	000	2	1/30/2024	NON-COMPETING CONTINUATION	$39,408
														Subtotal = $40,688

Issue Date FY: 2023 ( Subtotal = $36,837 )
2023	2023	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Cardiovascular Diseases Research	000	1	1/13/2023	NEW	$35,895
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cardiovascular Diseases Research	001	1	3/14/2023	NEW	$942
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cardiovascular Diseases Research	002	1	3/14/2023	NEW	$0
														Subtotal = $36,837

Grand Total All Awards = $88,656

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Metabolic Control of Epigenetic Reprogramming in Neovascularization

Award Number: F30HL167457

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 05/17/2025

AWARD TERMINATION DATE: 09/05/2026

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