Thursday, July 3, 2025 7/3/2025

Cysteine oxidation in the heart

Award Number: R01HL091469
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2008
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Cysteine oxidation in the heart - Summary Oxidative stress affects the function of signaling molecules through posttranslational modifications of cysteine residues, which in turn regulate survival and death of cardiomyocytes (CMs) during myocardial stress. We have shown that thioredoxin1 (Trx1), a 12 kD oxidoreductase, modulates the function of signaling molecules, including HDAC4, AMPK, mTOR, and Atg7, in the heart by modulating their cysteine residues through either thiol-disulfide exchange or transnitrosylation. Here we will investigate a novel role of cysteine oxidation in mediating the degradation of sarcoplasmic reticulum (SR)/endoplasmic reticulum (ER) Ca2+ ATPase 2a (SERCA2a) during heart failure and its regulation through non-canonical interaction between p22phox, SERCA2a and Trx1. SERCA2a mediates Ca2+ reuptake into the SR/ER. Reduced contractility in the failing heart caused by impaired Ca2+ cycling between the sarcoplasm and SR and SERCA2a downregulation are important drivers of heart failure progression. Although rescue of SERCA2a using adeno-associated virus 9 (AAV9)-mediated delivery is effective in animals, it does not appear fully effective in heart failure patients. Complex posttranslational modifications of SERCA2a, including oxidation, acetylation and SUMOylation, may not allow effective restoration of SERCA2a function with the current strategy. Oxidation of SERCA2a induces proteolysis through the ubiquitin proteasome system. We discovered that mice with cardiac-specific deletion of p22phox are more susceptible to heart failure during pressure overload (PO) even though bulk production of reactive oxygen species is attenuated. In depth studies of the underlying mechanism suggest that endogenous p22phox binds to SERCA2a, protects SERCA2a from oxidation of cysteine residues, including Cys498, and prevents Smurf1/Hrd1-mediated proteasome degradation of SERCA2a during oxidative stress in vitro. These results suggest that p22phox plays a previously unrecognized role in the regulation of the function of SERCA2a function through direct interaction. We will test the following hypotheses: 1. p22phox protects the heart against heart failure in response to PO by stabilizing SERCA2a through direct interaction. 2. p22phox stabilizes SERCA2a against oxidative stress by mediating SERCA2a-Trx1 interaction, inhibiting oxidation of SERCA2a cysteines, including Cys498, and preventing SERCA2a-Smurf1/Hrd1 interaction. To test these hypotheses, we will use newly generated genetically altered mouse models, including p22phox cardiac specific knock-out and SERCA2a(C498S) knock-in mice. We will use proteomic approaches to evaluate posttranslational modification of cysteine residues in SERCA2a and demonstrate thiol-disulfide exchange between SERCA2a and Trx1. Our study will not only demonstrate a novel noncanonical function of p22phox but also clarify the detailed mechanism through which oxidation of SERCA2a at previously unrecognized cysteine residues leads to proteasomal degradation during PO. The study will provide useful information for efficient restoration of SERCA2a function during heart failure through modulation of cysteine oxidation.


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 = $546,094 )
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	001	17	4/17/2025	NON-COMPETING CONTINUATION	$546,094
2025	2022	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	15	2/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $546,094

Issue Date FY: 2024 ( Subtotal = $606,770 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	000	16	6/1/2024	COMPETING CONTINUATION	$606,770
														Subtotal = $606,770

Issue Date FY: 2022 ( Subtotal = $558,624 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	15	6/17/2022	NON-COMPETING CONTINUATION	$55,866
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	15	2/20/2022	NON-COMPETING CONTINUATION	$502,758
														Subtotal = $558,624

Issue Date FY: 2021 ( Subtotal = $558,624 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	14	2/26/2021	NON-COMPETING CONTINUATION	$558,624
														Subtotal = $558,624

Issue Date FY: 2020 ( Subtotal = $558,624 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	13	2/19/2020	NON-COMPETING CONTINUATION	$558,624
														Subtotal = $558,624

Issue Date FY: 2019 ( Subtotal = $558,624 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	12	2/20/2019	COMPETING CONTINUATION	$558,624
2019	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	11	7/3/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $558,624

Issue Date FY: 2018 ( Subtotal = -$136,384 )
2018	2015	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	002	9	3/16/2018	NON-COMPETING CONTINUATION	$0
2018	2013	UNIVERSITY OF MEDICINE AND DENTISTRY OF NJ (INC)							Cardiovascular Diseases Research	003	6	9/30/2018	COMPETING CONTINUATION	-$136,383
2018	2013	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	7	3/16/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$136,384
2018	2013	UNIVERSITY OF MEDICINE AND DENTISTRY OF NJ (INC)							Cardiovascular Diseases Research	000	6	3/16/2018	COMPETING CONTINUATION	$136,383
														Subtotal = -$136,384

Issue Date FY: 2017 ( Subtotal = $532,923 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	11	2/15/2017	NON-COMPETING CONTINUATION	$532,923
														Subtotal = $532,923

Issue Date FY: 2016 ( Subtotal = $532,923 )
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	000	10	2/25/2016	EXTENSION WITH OR WITHOUT FUNDS	$532,923
														Subtotal = $532,923

Issue Date FY: 2015 ( Subtotal = $524,929 )
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	000	9	3/4/2015	NON-COMPETING CONTINUATION	$524,929
														Subtotal = $524,929

Issue Date FY: 2014 ( Subtotal = $522,264 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	000	8	3/8/2014	NON-COMPETING CONTINUATION	$522,264
2014	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	001	6	4/21/2014	COMPETING CONTINUATION	$47,844
2014	2013	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	002	7	4/21/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$47,844
														Subtotal = $522,264

Issue Date FY: 2013 ( Subtotal = $531,806 )
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Cardiovascular Diseases Research	002	7	8/12/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$395,422
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	005	6	4/21/2014	COMPETING CONTINUATION	$47,844
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	001	6	1/25/2013	COMPETING CONTINUATION	$531,806
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Cardiovascular Diseases Research	004	7	4/21/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$47,844
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	003	6	8/12/2013	COMPETING CONTINUATION	-$395,422
2013	2012	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	000	5	1/23/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $531,806

Issue Date FY: 2012 ( Subtotal = $527,236 )
2012	2012	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	000	5	2/16/2012	NON-COMPETING CONTINUATION	$527,236
														Subtotal = $527,236

Issue Date FY: 2011 ( Subtotal = $532,412 )
2011	2011	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	001	4	7/14/2011	NON-COMPETING CONTINUATION	$35,917
2011	2011	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	000	4	12/16/2010	NON-COMPETING CONTINUATION	$496,495
														Subtotal = $532,412

Issue Date FY: 2010 ( Subtotal = $537,790 )
2010	2010	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	001	3	3/3/2010	NON-COMPETING CONTINUATION	$43,901
2010	2010	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	000	3	12/25/2009	NON-COMPETING CONTINUATION	$493,889
														Subtotal = $537,790

Issue Date FY: 2009 ( Subtotal = $540,949 )
2009	2009	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	001	2	4/3/2009	NON-COMPETING CONTINUATION	$54,095
2009	2009	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	000	2	1/1/2009	NON-COMPETING CONTINUATION	$486,854
														Subtotal = $540,949

Issue Date FY: 2008 ( Subtotal = $537,515 )
2008	2008	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	000	1	1/15/2008	NEW	$537,515
														Subtotal = $537,515

Grand Total All Awards = $8,571,723

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Cysteine oxidation in the heart

Award Number: R01HL091469

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2008

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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