Monday, November 25, 2024 11/25/2024

Regulation of myocardial growth and death by GSK-3

Award Number: R01HL067724
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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DESCRIPTION (provided by applicant): Glycogen synthase kinase (GSK) -3α and -3β are unique protein kinases in that they are active in cells under unstimulated conditions but are inhibited by phosphorylation of specific N-terminal serine residues. Constitutive activation of GSK-3β attenuates cardiac hypertrophy and dysfunction in response to pressure overload, whereas constitutive activation of GSK-3α exacerbates them, suggesting that GSK-3α and GSK-3β have distinct functions in the heart. Despite their structural similarity, GSK-3α and GSK-3β have distinct, subcellularly compartmentalized, and often opposite, functions. Our long term goal is to elucidate the isoform-specific functions of GSK-3α/β in the heart. Here we will focus on the novel function of GSK-3α in mediating cardiac dysfunction in response to obesity and insulin resistance. GSK-3α is activated in the hearts of obese mice fed a high-fat diet (HFD). Activation of GSK-3α in the nucleus phosphorylates PPARα at S280 in the ligand-binding domain (LBD) and stimulates the transcriptional activity of PPARα. Together with the fact that haploinsufficiency of GSK-3α protects the heart from cardiac hypertrophy and diastolic dysfunction in response to HFD, these findings suggest that GSK-3α is involved in the pathogenesis and development of cardiac dysfunction in response to obesity and insulin resistance through S280 phosphorylation of PPARα. Our overall hypothesis is that GSK-3α excessively activates PPARα transcriptional activity through phosphorylation of PPARα at S280 and enhanced heterodimerization with RXRα, thereby causing metabolic derangement in the heart subjected to obesity or insulin resistance. Synthetic ligands for PPARα prevent S280 phosphorylation by interfering with GSK-3α-PARα interaction at the LBD, thereby alleviating metabolic derangement in response to HFD. To test this hypothesis, we will use cardiac-specific GSK-3α knock-out mice and mice expressing PPARα 280 phosphorylation-resistant and -mimicking mutants in combination with proteomic approaches and metabolic analyses. The knowledge obtained from this study should be useful for developing new specific strategies to limit myocardial damage in patients with obesity or insulin resistance through specific modulation of GSK-3α and /or S280 phosphorylation of PPARα.


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: 2022 ( Subtotal = -$531 )
2022	2018	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	18	6/29/2022	NON-COMPETING CONTINUATION	-$531
2022	2017	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	17	6/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = -$531

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	18	4/22/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $357,750 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	18	5/25/2018	NON-COMPETING CONTINUATION	$7,155
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	18	12/6/2017	NON-COMPETING CONTINUATION	$350,595
														Subtotal = $357,750

Issue Date FY: 2017 ( Subtotal = $357,750 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	17	11/30/2016	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2016 ( Subtotal = $357,750 )
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	001	16	2/11/2016	NON-COMPETING CONTINUATION	$35,775
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	000	16	11/4/2015	NON-COMPETING CONTINUATION	$321,975
														Subtotal = $357,750

Issue Date FY: 2015 ( Subtotal = $357,750 )
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	001	15	11/4/2014	COMPETING CONTINUATION	$357,750
2015	2013	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	000	14	10/30/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $357,750

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2013	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	000	14	3/13/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $330,810 )
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	002	13	8/16/2013	NON-COMPETING CONTINUATION	-$262,542
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	000	13	2/19/2013	NON-COMPETING CONTINUATION	$312,741
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	001	13	6/25/2013	NON-COMPETING CONTINUATION	$18,069
2013	2013	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	004	14	3/13/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Cardiovascular Diseases Research	003	14	8/16/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$262,542
														Subtotal = $330,810

Issue Date FY: 2012 ( Subtotal = $347,490 )
2012	2012	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	000	12	3/6/2012	NON-COMPETING CONTINUATION	$347,490
														Subtotal = $347,490

Issue Date FY: 2011 ( Subtotal = $351,000 )
2011	2011	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	000	11	4/7/2011	NON-COMPETING CONTINUATION	$351,000
														Subtotal = $351,000

Issue Date FY: 2010 ( Subtotal = $351,000 )
2010	2010	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	001	10	2/19/2010	COMPETING CONTINUATION	$351,000
2010	2008	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Cardiovascular Diseases Research	000	9	2/17/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $351,000

Issue Date FY: 2008 ( Subtotal = $258,024 )
2008	2008	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Cardiovascular Diseases Research	000	9	8/18/2008	NON-COMPETING CONTINUATION	$258,024
														Subtotal = $258,024

Issue Date FY: 2007 ( Subtotal = $258,024 )
2007	2007	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Cardiovascular Diseases Research	000	8	8/20/2007	NON-COMPETING CONTINUATION	$258,024
														Subtotal = $258,024

Issue Date FY: 2006 ( Subtotal = $265,731 )
2006	2006	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Cardiovascular Diseases Research	000	7	8/14/2006	NON-COMPETING CONTINUATION	$265,731
														Subtotal = $265,731

Issue Date FY: 2005 ( Subtotal = $272,125 )
2005	2005	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Cardiovascular Diseases Research	000	6	7/29/2005	NON-COMPETING CONTINUATION	$272,125
														Subtotal = $272,125

Issue Date FY: 2004 ( Subtotal = $272,125 )
2004	2004	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Cardiovascular Diseases Research	000	5	7/26/2004	COMPETING CONTINUATION	$272,125
														Subtotal = $272,125

Issue Date FY: 2003 ( Subtotal = $235,500 )
2003	2003	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	30 BERGEN ST, ADM BLDG #11	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	000	4	9/11/2003	NON-COMPETING CONTINUATION	$235,500
														Subtotal = $235,500

Issue Date FY: 2002 ( Subtotal = $235,500 )
2002	2002	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	30 BERGEN ST, ADM BLDG #11	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	000	3	8/6/2002	NON-COMPETING CONTINUATION	$235,500
														Subtotal = $235,500

Issue Date FY: 2001 ( Subtotal = $235,500 )
2001	2001	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	30 BERGEN ST, ADM BLDG #11	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	000	2	7/10/2001	NON-COMPETING CONTINUATION	$235,500
														Subtotal = $235,500

Issue Date FY: 2000 ( Subtotal = $235,500 )
2000	2000	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Cardiovascular Diseases Research	000	1	9/27/2000	NEW	$235,500
														Subtotal = $235,500

Grand Total All Awards = $5,078,798

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Regulation of myocardial growth and death by GSK-3

Award Number: R01HL067724

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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