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Regulation of CSE-Derived Hydrogen Sulfide in the Heart

Award Number: R01HL164806
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: 03/31/2027

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Regulation of CSE-Derived Hydrogen Sulfide in the Heart - Project Summary Hydrogen sulfide (H2S) is an endogenously produced signaling molecule that impacts protein function by modifying cysteine residues through the formation of a persulfide bond by a process termed sulfhydration (persulfidation). It is produced enzymatically by three enzymes in the cysteine biosynthesis pathway: cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercaptopyruvate sulfutransferase (3- MST). Numerous studies have reported a protective role for H2S in experimental models of acute myocardial ischemia-reperfusion injury and heart failure. While these studies and others have established a cytoprotective role for H2S, there are still unresolved questions regarding the biology of H2S. For instance, there is a lack of understanding in how the endogenous production of H2S is regulated. Additionally, there is a need to identify protein targets of H2S in response to different stimuli to unravel the mechanism by with H2S impacts adaptation to stress. This proposal aims to offer new insights into the regulation of the H2S-producing activity of CSE. We present new data that AMP-activated protein kinase (AMPK) increases CSE-derived H2S production via phosphorylation of serine 126. Further studies identified perilipin 5 (Plin5) – a protein that promotes the association of lipid droplets with mitochondria - as a protein modified by sulfhydration following nutrient deprivation and AMPK activation. Our data also shows that the interaction of lipid droplets with mitochondria following nutrient deprivation is dependent on CSE. Based on this evidence, we hypothesize that in response to nutrient stress, AMPK induces the H2S-producing activity of CSE to impart adaptive cellular mechanisms. Specifically, we hypothesize that CSE-derived H2S maintains energy metabolism during nutrient stress by regulating the mobilization of lipid droplets to the mitochondria, in part, by altering the sulfhydration of Plin5. In Aim 1, we will investigate the impact of serine 126 phosphorylation on the H2S-producing activity of CSE. In Aim 2, we will investigate the Impact of CSE-derived H2S on maintaining Lipid Droplet-fueled β-oxidation during nutrient deprivation. In Aim 3, we will determine the impact of sulfhydration on Plin5 during nutrient deprivation. This project breaks new ground in defining a mechanism by which the H2S-producing activity of CSE is regulated. As such, it has the potential to lead to the development of novel therapies aimed at harnessing the physiological effects of H2S to combat cardiovascular disease.


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 = $514,162 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Cardiovascular Diseases Research	000	4	3/20/2026	NON-COMPETING CONTINUATION	$514,162
														Subtotal = $514,162

Issue Date FY: 2025 ( Subtotal = $524,654 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Cardiovascular Diseases Research	000	3	4/15/2025	NON-COMPETING CONTINUATION	$472,188
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Cardiovascular Diseases Research	001	3	7/16/2025	NON-COMPETING CONTINUATION	$52,466
														Subtotal = $524,654

Issue Date FY: 2024 ( Subtotal = $514,162 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Cardiovascular Diseases Research	001	2	6/20/2024	NON-COMPETING CONTINUATION	$41,974
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cardiovascular Diseases Research	000	2	3/5/2024	NON-COMPETING CONTINUATION	$472,188
														Subtotal = $514,162

Issue Date FY: 2023 ( Subtotal = $521,524 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cardiovascular Diseases Research	000	1	3/31/2023	NEW	$521,524
														Subtotal = $521,524

Grand Total All Awards = $2,074,502

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Regulation of CSE-Derived Hydrogen Sulfide in the Heart

Award Number: R01HL164806

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: 03/31/2027

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