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Novel roles of PDK2 in heart failure: Regulation of mitochondrial nuclear crosstalk via metabolic regulation and histone acetylation

Award Number: R01HL167872
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Novel roles of PDK2 in heart failure: Regulation of mitochondrial nuclear crosstalk via metabolic regulation and histone acetylation - PROJECT SUMMARY/ABSTRACT Cardiovascular disease is the leading cause of death in the world. Changes in cardiac metabolic substrate utilization underlie, and may play a causative role in, the development of heart failure. A critical point of regulation in the ability of the heart to fully oxidize glucose is that of the pyruvate dehydrogenase (PDH) complex that, in the heart, is negatively regulated by phosphorylation mediated by two PDH kinases (PDK2 and PDK4). PDKs are differentially regulated in response to physiological stimuli (e.g., exercise) and pathological stimuli (e.g., heart failure). Therefore, they represent likely candidates for therapeutic intervention. However, early attempts to regulate the PDKs have not fully tested the individual isoforms. A long-term goal of our laboratory is to understand the role of these different isoforms in the progression of heart failure. Our preliminary data using germline knockout mice for either of these isoforms in a pressure-overload induced model of heart failure, provides compelling data for a protective role for loss of Pdk2, and an exacerbated role for loss of Pdk4. Furthermore, our initial characterization identified several PDK isoform specific molecular differences, including higher protein acetylation in Pdk2-/- hearts and a higher mortality in Pdk4-/- mice. We also provide evidence to support a mechanism by which the differential acetylation is targeted to the nucleus and may play a role in the histone code, linking it to epigenetic regulation of gene expression. A critical barrier in determining the molecular mechanisms of these PDK isoforms has been the ability to examine each individually. To overcome this barrier, we have generated inducible cardiomyocyte specific knockouts to test the tissue-specific roles of these kinases in adult hearts. The objective of the current proposal is to test the hypothesis that loss of PDK2, but not PDK4, is cardioprotective through differential epigenetic (histone protein acetylation) and transcriptional regulation in response to pressure-overload induced heart failure. We have developed two novel mouse models to test this hypothesis. In this proposal we will: determine the role of each PDK isoform in heart failure progression (Aim 1) and identify molecular mechanisms of these differences (Aim 2). Collectively, the completion of these studies will provide fundamental insights into the mechanistic basis for individual PDK isoforms in the regulation of cardiac gene expression contributing to the development of heart failure.


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 = $417,024 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	3	3/28/2025	NON-COMPETING CONTINUATION	$417,024
														Subtotal = $417,024

Issue Date FY: 2024 ( Subtotal = $454,093 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	2	6/20/2024	NON-COMPETING CONTINUATION	$37,069
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	2	3/4/2024	NON-COMPETING CONTINUATION	$417,024
														Subtotal = $454,093

Issue Date FY: 2023 ( Subtotal = $463,360 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	1	3/9/2023	NEW	$463,360
														Subtotal = $463,360

Grand Total All Awards = $1,334,477

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Novel roles of PDK2 in heart failure: Regulation of mitochondrial nuclear crosstalk via metabolic regulation and histone acetylation

Award Number: R01HL167872

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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