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Glucose-Mediated Remodeling of Cardiac DNA Methylation

Award Number: R01HL133011
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2022

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Glucose-Mediated Remodeling of Cardiac DNA Methylation - Despite overall reductions in heart disease, the increased risk of developing heart failure has remained 2-fold greater among people with diabetes. Evidence from our laboratory and others has identified that fluctuations in glucose level and uptake directly contributes to cardiovascular disease (CVD) by modifying proteins, DNA, and gene expression. In the case of glucose, clinical studies have shown that following tight glycemic control, susceptibility to disease progression is sustained years or even decades in a process termed “glycemic memory”. A long-term goal of our laboratory is to understand the role of glucose in the formation of glycemic memory and determine if these changes alter disease progression. Recently the mechanism of epigenetic regulation, which consists of modifications of the histone proteins that help package DNA and direct modifications of the DNA (e.g. methylation), is linked to glycemic memory. A critical barrier in determining the molecular mechanisms has been the ability to place the marks in the intact heart to test disease susceptibility. Two novel advances have taken place over the last 2-5 years that place the glucose-mediated protein post-translational modification, O-GlcNAcylation, at the forefront of this quest. Specifically, O- GlcNAcylation is part of the histone code. Secondly, the proteins that regulate O-GlcNAcylation interact with the proteins that tailor DNA methylation, providing a second link between glucose and epigenetics. The objective of the current proposal is to determine the mechanism by which fluctuations in glucose alter DNA methylation and how these changes alter gene expression and cardiac function. As diabetes and heart failure are diseases with strong metabolic components, we will focus on how glucose-mediated epigenetic changes alter metabolism and energetics in acquired heart disease. We have developed two novel mouse models to test this hypothesis. The first builds upon our model of inducible cardiomyocyte-specific expression of the glucose transporter, GLUT4, and the second is a new model of cardiomyocyte O-GlcNAc regulation. Thus uniquely allowing us to directly test the role that cardiomyocyte glucose delivery and GlcNAcylation have on CVD. Our preliminary data define persistent DNA methylation changes that increase susceptibility to pressure- overload hypertrophy. In this proposal we will: determine the mechanism of altered DNA methylation (Aim 1), determine if these epigenetic modifications alter contractile and metabolic dysfunction in response to a common diabetic co-morbidity of hypertension (Aim 2), and determine if O-GlcNAc alone is sufficient to increase disease susceptibility (Aim 3). Collectively, the completion of these studies will provide fundamental insights into the mechanistic basis for glucose in the regulation of cardiac gene expression contributing to the development of diabetic CVD.


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: 2023 ( Subtotal = -$5,501 )
2023	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	9/12/2023	NON-COMPETING CONTINUATION	-$5,501
														Subtotal = -$5,501

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	4	7/20/2020	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2019 ( Subtotal = $371,250 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	3	8/6/2019	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2018 ( Subtotal = $407,463 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	2	8/21/2018	NON-COMPETING CONTINUATION	$371,250
2018	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	1	1/9/2018	NEW	$36,213
														Subtotal = $407,463

Issue Date FY: 2017 ( Subtotal = $371,250 )
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	1	4/20/2017	NEW	$3,750
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	1	3/27/2017	NEW	$367,500
														Subtotal = $371,250

Grand Total All Awards = $1,515,712

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Glucose-Mediated Remodeling of Cardiac DNA Methylation

Award Number: R01HL133011

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2022

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