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Role of PHLPP in the Heart

Award Number: R01HL114949
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2014
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Role of PHLPP in the Heart - Summary/Abstract Cardiovascular disease is the leading cause of death in the United States. One factor that increases the incidence of heart failure is aging. Several clinical reports have highlighted how physiological processes that regulate proper functioning of cardiac tissue decline as individual ages. One of these processes is regulated by the actions of PHLPP, a serine/threonine phosphatase that has been shown to regulate cell growth and survival through dephosphorylation of several members of the AGC kinase family including Akt. The levels of PHLPP expression have been associated with several diseases that are correlated with aging including cancer, diabetes and cardiovascular disease. With age, neurohormonal signaling like Akt becomes chronically activated. The role of PHLPP2 in cardiovascular pathology and the role of aging are unknown. Studies in this proposal will examine the mechanism of PHLPP2 protein expression with age and its effect on post- translational and epigenetic modifications. We hypothesize that PHLPP2 levels are altered with age and regulate epigenetic changes to influence transcriptional networks important for cellular homeostasis. We have demonstrated for the first time a novel interaction between PHLPP2 and the G-protein coupled receptor kinase 5 (GRK5) to regulate phenylephrine induced cardiomyocyte growth. Next generation sequencing uncovered transcriptional networks altered in the heart by PHLPP2 removal that regulates growth factor receptor signaling and metabolic processes. Mitochondria are critical for the energy required by the heart, and therefore, play an important role in survival and function of the cardiomyocytes. In the first aim using young and aged wild-type and PHLPP2 KO mice we will determine the mechanism of the regulation of PHLPP2 isoform expression in the heart with age and its effect on mitochondrial function basally and following ischemic injury. Aim two will investigate the effect of posttranslational modification of GRK5 by PHLPP2 on its ability to regulate cardiac hypertrophy signaling. Lastly, in aim three we will define the epigenetic mechanisms required for PHLPP2 mediated regulation of transcriptional changes in vitro and in vivo that is important for cardiac homeostasis. Using both in vitro and in vivo systems we aim to test the proposed hypothesis and significantly impact our current understanding of cardiac outcome associated with epigenetic modifications. The long-term goal of this proposal is determine novel targets of PHLPP2 and uncover its mechanism of action in regulating cardiac growth and metabolic signaling with aging.


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 = $0 )
2024	2022	HUNTINGTON MEDICAL RESEARCH INSTITUTES	686 S FAIR OAKS AVE	PASADENA	CA	91105	LOS ANGELES	USA	Cardiovascular Diseases Research	000	9	8/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $432,233 )
2022	2022	HUNTINGTON MEDICAL RESEARCH INSTITUTES	686 S FAIR OAKS AVE	PASADENA	CA	91105	LOS ANGELES	USA	Cardiovascular Diseases Research	003	9	6/29/2022	NON-COMPETING CONTINUATION	$43,226
2022	2022	HUNTINGTON MEDICAL RESEARCH INSTITUTES	686 S FAIR OAKS AVE	PASADENA	CA	91105	LOS ANGELES	USA	Cardiovascular Diseases Research	002	9	4/15/2022	NON-COMPETING CONTINUATION	$389,007
2022	2021	HUNTINGTON MEDICAL RESEARCH INSTITUTES	686 S FAIR OAKS AVE	PASADENA	CA	91105	LOS ANGELES	USA	Cardiovascular Diseases Research	001	8	4/13/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$215,788
2022	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	7	4/13/2022	NON-COMPETING CONTINUATION	-$215,788
														Subtotal = $432,233

Issue Date FY: 2021 ( Subtotal = $432,233 )
2021	2021	HUNTINGTON MEDICAL RESEARCH INSTITUTES	686 S FAIR OAKS AVE	PASADENA	CA	91105	LOS ANGELES	USA	Cardiovascular Diseases Research	001	8	6/10/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$432,233
2021	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	7	6/9/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $432,233

Issue Date FY: 2020 ( Subtotal = $442,632 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	7	7/28/2020	NON-COMPETING CONTINUATION	$442,632
														Subtotal = $442,632

Issue Date FY: 2019 ( Subtotal = $442,397 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	6	4/5/2019	COMPETING CONTINUATION	$442,397
2019	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	002	5	7/10/2019	NON-COMPETING CONTINUATION	$0
2019	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	5	4/4/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $442,397

Issue Date FY: 2018 ( Subtotal = $387,500 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	5	1/26/2018	NON-COMPETING CONTINUATION	$379,750
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	5	7/14/2018	NON-COMPETING CONTINUATION	$7,750
														Subtotal = $387,500

Issue Date FY: 2017 ( Subtotal = $387,500 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	4	1/17/2017	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2016 ( Subtotal = $387,500 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	3	2/8/2016	NON-COMPETING CONTINUATION	$5,813
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	3	1/15/2016	NON-COMPETING CONTINUATION	$381,687
														Subtotal = $387,500

Issue Date FY: 2015 ( Subtotal = $381,687 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	2	1/27/2015	NON-COMPETING CONTINUATION	$381,687
														Subtotal = $381,687

Issue Date FY: 2014 ( Subtotal = $387,500 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	1	3/11/2014	NEW	$38,750
2014	2014	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	1	1/16/2014	NEW	$348,750
														Subtotal = $387,500

Grand Total All Awards = $3,681,182

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Role of PHLPP in the Heart

Award Number: R01HL114949

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2014

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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