Monday, November 3, 2025 11/3/2025

Regulation of Vascular Smooth Muscle Cell Phenotype by a Novel Isoform of Glucose-6-Phosphate Dehydrogenase

Award Number: R01HL166546
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Regulation of Vascular Smooth Muscle Cell Phenotype by a Novel Isoform of Glucose-6-Phosphate Dehydrogenase - Vascular diseases continue to be a major cause of death in the US and worldwide. It has been proposed that metabolic reprogramming and increased glucose-6-phosphate dehydrogenase (G6PD) activity and expression contribute to the pathogenesis of fatal angioproliferative vasculopathies. Moreover, some studies suggest individuals with a loss-of- function G6PD (Mediterranean or African) variant – S188F (G6PDS188F; Type A-; severe deficiency) or N126D (G6PDN126D; Type A; mild deficiency) nonsynonymous single nucleotide polymorphism – have lower frequencies of coronary artery disease. However, G6PD-driven pathogenic and G6PD variant-associated protective mechanisms affecting vascular diseases remain elusive. We therefore propose to determine potential mechanisms, driven by a newly discovered G6PD isoform in the nucleus of vascular smooth muscle cells (VSMCs), that contribute to pathogenic large artery stiffness and remodeling. Based on strongly supporting preliminary results, we hypothesized that nuclear G6PD is a modulator of epigenetic modifiers and is a transcription regulator in VSMCs. Consequently, the loss-of-function G6PD (S188F, N126D) variants block maladaptive modifications of the epigenome, reducing large artery elastance and remodeling elicited by obesity/metabolic syndrome and balloon-injury. We will test this hypothesis in three specific aims. In Aim 1, we will test the hypothesis that G6PD and/or G6PD-coordinated redox in the nucleus controls the expression and activity of epigenetic modifiers (DNA methyltransferases (DNMT) and DNA (TET) and histone (JARID) demethylases) and transcription of genes that encode proteins involved in regulating the differentiation (contractile) and dedifferentiation (pro-inflammatory, -thrombotic, and -proliferative) phenotypes in VSMCs. In Aim 2, we will determine whether loss-of-function G6PD variants detach from epigenetic modifiers to increase DNA methylation, suppress histone3-lysine4 trimethylation, and reduce transcription of genes that confer maladaptive (pro- inflammatory, -thrombotic, and -proliferative) properties to VSMCs. In Aim 3, we will determine whether G6PD variant rats express fewer maladaptive epigenetic (histone3-lysine4 trimethylation) changes and develop less large artery elastance (stiffness) and vascular remodeling than wild-type rats fed a high-fat diet (a model of obesity/metabolic syndrome) or subjected to carotid artery balloon-injury. The results from gain-of-function and loss-of-function studies of this project will reveal the direct effect of G6PD on gene expression associated with pathogenic vascular remodeling and large artery stiffness, which lead to heart failure and death. We foresee two significant impacts on vascular biology: [1] linkage of heretofore unknown G6PD-dependent subcellular redox in the nucleus directly to the fundamental transcriptional mechanics and gene transcription in vascular pathobiology and [2] development of new treatments targeting redox signaling to reduce large artery stiffness and remodeling.


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 = $689,459 )
2025	2025	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	000	3	11/15/2024	NON-COMPETING CONTINUATION	$620,514
2025	2025	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	001	3	8/19/2025	NON-COMPETING CONTINUATION	$68,945
														Subtotal = $689,459

Issue Date FY: 2024 ( Subtotal = $675,671 )
2024	2024	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	001	2	6/26/2024	NON-COMPETING CONTINUATION	$55,157
2024	2024	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	000	2	11/9/2023	NON-COMPETING CONTINUATION	$620,514
														Subtotal = $675,671

Issue Date FY: 2023 ( Subtotal = $705,459 )
2023	2023	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Cardiovascular Diseases Research	000	1	12/9/2022	NEW	$705,459
														Subtotal = $705,459

Grand Total All Awards = $2,070,589

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Regulation of Vascular Smooth Muscle Cell Phenotype by a Novel Isoform of Glucose-6-Phosphate Dehydrogenase

Award Number: R01HL166546

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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