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REGULATION OF MYOCARDIAL GROWTH AND DEATH BY THE HIPPO PATHWAY

Award Number: R01HL112330
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2012
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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REGULATION OF MYOCARDIAL GROWTH AND DEATH BY THE HIPPO PATHWAY - Summary The Hippo signaling pathway is an evolutionarily conserved signaling pathway that controls organ size and tumorigenesis by regulating cell growth and death. We have shown that each component of the Hippo pathway is intimately involved in the pathogenesis of heart failure. YAP, the nuclear effector of the Hippo pathway, is transiently activated in response to pressure overload (PO) but downregulated during the chronic phase of PO and heart failure. Cardiac specific downregulation of YAP inhibits cardiac hypertrophy but promotes heart failure during the acute phase of PO, suggesting that endogenous YAP is salutary and mediates compensatory hypertrophy during the acute phase of PO. Although YAP is downregulated during the chronic phase of PO, forced activation of YAP at this stage is detrimental and promotes heart failure, due to de-differentiation of cardiomyocytes. Thus, YAP can be either protective or detrimental in a context-dependent manner during PO. However, it remains to be shown what makes YAP either salutary or detrimental during PO in the heart. Our preliminary results suggest that YAP promotes compensatory cardiac hypertrophy by stimulating glycolysis through upregulation of GLUT1 in the heart during the acute phase of PO, in a manner similar to aerobic glycolysis, namely the “Warburg effects” in cancer cells. Here we hypothesize that endogenous YAP mediates compensatory hypertrophy and survival of cardiomyocytes in the presence of PO through transcription of GLUT1 and consequent upregulation of glycolysis and biosynthetic molecules. YAP acts cooperatively with TEAD and HIF-1 and is involved in upregulation of GLUT1 that is activated during the acute phase of PO but inactivated during the chronic phase of PO due to differential availability of the partner transcription factors of YAP. To test these hypotheses, we will: 1. (a) Demonstrate that endogenous YAP plays an essential role in mediating upregulation of glycolysis in response to acute PO. (b) Demonstrate that activation of YAP induces accumulation of glycolytic intermediates through GLUT1- and PKM2-dependent mechanisms. (c) Demonstrate that YAP-induced upregulation of GLUT1 is essential for the maintenance of glycolysis and consequent upregulation of compensatory cardiac hypertrophy in response to acute PO. 2. Demonstrate that YAP-induced upregulation of GLUT1 is mediated through direct binding of YAP to TEAD and/or HIF-1 and resultant cooperative actions during acute PO. We will use genetically altered mouse models, cultured adult cardiomyocytes, metabolomic analyses, transcriptome analyses and ChIP sequencing analyses to address these issues. Successful completion of this project will provide novel information about the molecular switch that controls the glycolytic pathway and compensatory hypertrophy in the heart and how YAP differentially controls signaling mechanisms to mediate both salutary and detrimental effects in the heart during PO.


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: 2024 ( Subtotal = $569,652 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	000	14	1/6/2024	NON-COMPETING CONTINUATION	$523,150
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	003	14	6/21/2024	NON-COMPETING CONTINUATION	$46,502
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	002	13	4/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$386,788
2024	2022	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	12	4/15/2024	NON-COMPETING CONTINUATION	-$386,788
														Subtotal = $569,652

Issue Date FY: 2023 ( Subtotal = $581,277 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	001	13	2/26/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$581,277
2023	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	12	2/24/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $581,277

Issue Date FY: 2022 ( Subtotal = $581,277 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	003	12	5/31/2022	NON-COMPETING CONTINUATION	$58,126
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	12	1/14/2022	NON-COMPETING CONTINUATION	$523,151
2022	2021	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	002	11	3/9/2022	COMPETING CONTINUATION	$123,093
2022	2020	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	10	3/9/2022	NON-COMPETING CONTINUATION	-$123,093
														Subtotal = $581,277

Issue Date FY: 2021 ( Subtotal = $579,425 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	11	2/5/2021	COMPETING CONTINUATION	$521,485
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	003	11	8/5/2021	COMPETING CONTINUATION	$57,940
2021	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	10	1/28/2021	NON-COMPETING CONTINUATION	$0
2021	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	002	10	2/10/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $579,425

Issue Date FY: 2020 ( Subtotal = $515,761 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	10	2/24/2020	NON-COMPETING CONTINUATION	$515,761
														Subtotal = $515,761

Issue Date FY: 2019 ( Subtotal = $515,761 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	9	1/11/2019	NON-COMPETING CONTINUATION	$515,761
														Subtotal = $515,761

Issue Date FY: 2018 ( Subtotal = $515,761 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	8	12/5/2017	NON-COMPETING CONTINUATION	$505,445
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	002	8	6/1/2018	NON-COMPETING CONTINUATION	$10,316
2018	2016	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	6	2/23/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $515,761

Issue Date FY: 2017 ( Subtotal = $530,511 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	7	12/14/2016	COMPETING CONTINUATION	$530,511
														Subtotal = $530,511

Issue Date FY: 2016 ( Subtotal = $474,035 )
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	002	6	2/3/2016	EXTENSION WITH OR WITHOUT FUNDS	$7,006
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	001	6	12/14/2015	EXTENSION WITH OR WITHOUT FUNDS	$467,029
2016	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	PISCATAWAY	NJ	088545602	MIDDLESEX	USA	HHS Programs for Disaster Relief Appropriations Act - Non Construction	000	3	11/27/2015	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $474,035

Issue Date FY: 2015 ( Subtotal = $467,028 )
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	001	5	2/20/2015	NON-COMPETING CONTINUATION	$40,302
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	000	5	11/14/2014	NON-COMPETING CONTINUATION	$426,726
														Subtotal = $467,028

Issue Date FY: 2014 ( Subtotal = $544,157 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	HHS Programs for Disaster Relief Appropriations Act - Non Construction	000	3	11/22/2013	SUPPLEMENT FOR EXPANSION	$79,500
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	001	4	4/14/2014	NON-COMPETING CONTINUATION	$464,657
														Subtotal = $544,157

Issue Date FY: 2013 ( Subtotal = $442,864 )
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	003	2	8/16/2013	NON-COMPETING CONTINUATION	-$173,584
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	001	2	7/2/2013	NON-COMPETING CONTINUATION	$24,190
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	000	2	11/30/2012	NON-COMPETING CONTINUATION	$418,674
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Cardiovascular Diseases Research	002	3	8/16/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$173,584
														Subtotal = $442,864

Issue Date FY: 2012 ( Subtotal = $465,194 )
2012	2012	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	000	1	2/13/2012	NEW	$465,194
														Subtotal = $465,194

Grand Total All Awards = $6,782,703

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REGULATION OF MYOCARDIAL GROWTH AND DEATH BY THE HIPPO PATHWAY

Award Number: R01HL112330

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2012

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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