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Energetic State and Metabolic Remodeling in Cardiac Hypertrophy and Failure

Award Number: R01HL160969
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/14/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Energetic State and Metabolic Remodeling in Cardiac Hypertrophy and Failure - Pathological stresses, such as pressure overload in the left ventricles of patients with hypertension and aortic valve stenosis, cause cardiac hypertrophy, a major risk factor of congestive heart failure. Hypertrophic and failing hearts shift substrate utilization preference from fatty acids to glucose, ketone bodies, and others. However, the interplay between the energetic state and the mitochondrial/metabolic remodeling in the hypertrophic and failing remains incompletely understood. Most of the past studies are based on models with confounding conditions. F1Fo-ATP synthase is an essential enzyme complex that generates ATP in mitochondria, thus playing a central role in cellular energetics. Genetic defects of F1Fo-ATP synthase are rare but deadly because of dilated cardiomyopathy and neuromuscular disorders. How those patients with partial F1Fo-ATP synthase deficiencies respond to pathological stresses is unclear. It is documented that F1Fo-ATP synthase is impaired in pathological hearts from patients and animals. Our recent study revealed that enhancing F1Fo-ATP synthase structure/function using gene therapy restored cardiac function in the hypertrophied hearts, corroborating the concept of targeting F1Fo-ATP synthase as a novel protective therapy for heart failure. Our prior studies demonstrated that mice lacking F1Fo-ATP synthase assembly factors, such as ATPAF1, lead to F1Fo-ATP synthase deficiencies with cardiomyopathy. Therefore, our central hypothesis is that enhancing F1Fo-ATP synthase capacity to facilitate ATP production efficiency will mitigate mitochondrial disorders and the ensued cardiac hypertrophy and failure. We propose to test the central hypothesis with two aims. In aim 1, we will test that the F1Fo-ATP synthase deficiency is an amendable pathogenic factor in heart failure progression. Experiments will provide evidence to support that partial F1Fo- ATP synthase deficiency contributes to the pathological progression of heart failure, and gene therapies correcting the deficiency will slow the heart failure progression. In aim 2, we will define how F1Fo-ATP synthase capacities directly correlate to mitochondrial homeostasis and metabolic remodeling in cardiomyocytes of the adult heart. Therefore, this proposed project will provide definitive evidence to support innovative gene therapy and define the underpinning mechanisms. The proposed study will yield novel insights into the primary mechanisms underlying metabolic remodeling in cardiac pathological hypertrophy progression. The preclinical animal study will lay the groundwork for innovative gene therapies, which will significantly impact patient care.


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 = $484,713 )
2025	2025	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	000	4	8/6/2025	NON-COMPETING CONTINUATION	$484,713
														Subtotal = $484,713

Issue Date FY: 2024 ( Subtotal = $475,019 )
2024	2024	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	000	3	7/23/2024	NON-COMPETING CONTINUATION	$475,019
														Subtotal = $475,019

Issue Date FY: 2023 ( Subtotal = $489,968 )
2023	2023	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	000	2	6/30/2023	NON-COMPETING CONTINUATION	$489,968
														Subtotal = $489,968

Issue Date FY: 2022 ( Subtotal = $491,209 )
2022	2022	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	000	1	9/14/2022	NEW	$491,209
														Subtotal = $491,209

Grand Total All Awards = $1,940,909

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Energetic State and Metabolic Remodeling in Cardiac Hypertrophy and Failure

Award Number: R01HL160969

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/14/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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