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PKG and PKA Duo-Activation to Treat Cardiac Proteotoxicity

Award Number: R01HL072166
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2003
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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PKG and PKA Duo-Activation to Treat Cardiac Proteotoxicity - Project Summary/Abstract Heart disease and resultant heart failure remain a leading cause of death and disability in humans, with heart failure being the most expensive single diagnosis in US healthcare. Protein degradation by the ubiquitin-proteasome system (UPS) is pivotal to protein quantity and quality control in the cell. UPS dysfunction especially proteasome functional insufficiency and increased proteotoxic stress (IPTS) play a major pathogenic role in the progression from a large subset of heart disease to heart failure and, accordingly, proteasome enhancement promises to become a new strategy to battle heart disease with IPTS. Developing more effective therapeutics to enhance the proteasome, however, requires better understanding how proteasome function is regulated. Recent advance in cell biology excitingly unravels the proteasome as a nodal point for controlling UPS proteolytic function. For example, it is recently reported that the 19S proteasome subunit RPN6/PSMD11 can be specifically phosphorylated at Ser14 by cAMP-dependent kinase (PKA), resulting in marked increases in the proteolytic function of the proteasome in cultured cells. We have reported that cGMP-dependent kinase (PKG) activates the proteasome, facilitates proteasomal degradation of misfolded proteins and thereby protects against cardiac IPTS but the proteasome phosphosite(s) of PKG remains undefined. Phosphodiesterase (PDE) 1, an enzyme known to degrade both cGMP and cAMP and thereby suppress PKG and PKA, is upregulated in mouse and human failing hearts. We have discovered that PDE1 is increased in mouse hearts with IPTS and PDE1 inhibition (PDE1i) improves UPS performance in a PKA- and PKG-dependent manner and confers striking therapeutic benefits to a bona fide mouse model of heart disease with IPTS. We newly created the Rpn6S14A and Rpn6S14D gene knock-in mice and confirmed that proteasome activation by PKA is specifically blocked and mimicked in them, respectively. Our pilot studies reveal that elevating cGMP but not cAMP further increases myocardial 26S proteasome activities in the Rpn6S14D mice. Hence, we propose and this project will test the novel hypothesis that distinctive but complementary molecular mechanisms are taken by PKG and PKA to activate the proteasome such that dual activation of PKG and PKA can complementarily enhance proteasome proteolytic function and thereby protect against cardiac IPTS. We will identify proteasome phosphosite(s) responsible for the proteasome activation by PKG using tandem mass spectrometry based proteomics combined with biochemical and genetic interrogations, determine the role of proteasome phosphoregulation by PKA in PDE1i-induced protection against cardiac IPTS, and test the effects of PKG and PKA duo-activation on UPS performance and protection against cardiac IPTS. Completion of this project will not only delineate the molecular mechanism by which PKG regulates the proteasome but also provide comprehensive experimental basis for developing PKG and PKA duo-activation as a novel strategy to treat heart disease with IPTS, a large subset of heart disease in humans.


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 = $0 )
2025	2023	THE UNIVERSITY OF SOUTH DAKOTA	414 E CLARK ST	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	18	6/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $475,725 )
2023	2023	UNIVERSITY OF SOUTH DAKOTA	414 E CLARK ST	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	18	6/2/2023	NON-COMPETING CONTINUATION	$475,725
														Subtotal = $475,725

Issue Date FY: 2022 ( Subtotal = $484,772 )
2022	2022	THE UNIVERSITY OF SOUTH DAKOTA	414 E CLARK ST	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	17	6/30/2022	NON-COMPETING CONTINUATION	$484,772
														Subtotal = $484,772

Issue Date FY: 2021 ( Subtotal = $486,222 )
2021	2021	THE UNIVERSITY OF SOUTH DAKOTA	414 E CLARK ST	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	16	6/21/2021	NON-COMPETING CONTINUATION	$486,222
2021	2018	THE UNIVERSITY OF SOUTH DAKOTA	414 E CLARK ST	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	001	14	7/15/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $486,222

Issue Date FY: 2020 ( Subtotal = $496,540 )
2020	2020	THE UNIVERSITY OF SOUTH DAKOTA	414 E CLARK ST	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	001	15	9/1/2020	COMPETING CONTINUATION	$496,540
2020	2018	THE UNIVERSITY OF SOUTH DAKOTA	414 E CLARK ST	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	14	11/18/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $496,540

Issue Date FY: 2018 ( Subtotal = $362,500 )
2018	2018	THE UNIVERSITY OF SOUTH DAKOTA	414 E CLARK ST	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	14	12/6/2017	NON-COMPETING CONTINUATION	$355,250
2018	2018	THE UNIVERSITY OF SOUTH DAKOTA	414 E CLARK ST	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	001	14	5/25/2018	NON-COMPETING CONTINUATION	$7,250
														Subtotal = $362,500

Issue Date FY: 2017 ( Subtotal = $362,500 )
2017	2017	THE UNIVERSITY OF SOUTH DAKOTA	414 E CLARK ST	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	13	11/16/2016	NON-COMPETING CONTINUATION	$362,500
														Subtotal = $362,500

Issue Date FY: 2016 ( Subtotal = $362,500 )
2016	2016	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	001	12	2/11/2016	NON-COMPETING CONTINUATION	$36,250
2016	2016	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	12	11/2/2015	NON-COMPETING CONTINUATION	$326,250
														Subtotal = $362,500

Issue Date FY: 2015 ( Subtotal = $362,500 )
2015	2015	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	002	11	11/4/2014	COMPETING CONTINUATION	$362,500
2015	2013	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	001	10	10/31/2014	NON-COMPETING CONTINUATION	$0
2015	2013	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	10	10/28/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $362,500

Issue Date FY: 2013 ( Subtotal = $338,115 )
2013	2013	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	001	10	7/2/2013	NON-COMPETING CONTINUATION	$18,469
2013	2013	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	10	4/5/2013	NON-COMPETING CONTINUATION	$319,646
														Subtotal = $338,115

Issue Date FY: 2012 ( Subtotal = $355,163 )
2012	2012	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	9	3/27/2012	NON-COMPETING CONTINUATION	$355,163
														Subtotal = $355,163

Issue Date FY: 2011 ( Subtotal = $358,750 )
2011	2011	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	8	3/17/2011	NON-COMPETING CONTINUATION	$358,750
														Subtotal = $358,750

Issue Date FY: 2010 ( Subtotal = $358,750 )
2010	2010	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	7	3/22/2010	NON-COMPETING CONTINUATION	$358,750
														Subtotal = $358,750

Issue Date FY: 2009 ( Subtotal = $375,396 )
2009	2009	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Trans-NIH Recovery Act Research Support	004	6	6/3/2009	SUPPLEMENT FOR EXPANSION	$16,646
2009	2009	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	003	6	3/23/2009	COMPETING CONTINUATION	$358,750
2009	2007	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	001	5	12/16/2008	NON-COMPETING CONTINUATION	$0
2009	2007	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	5	12/11/2008	NON-COMPETING CONTINUATION	$0
2009	2007	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	002	5	3/23/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $375,396

Issue Date FY: 2007 ( Subtotal = $333,048 )
2007	2007	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	5	5/25/2007	NON-COMPETING CONTINUATION	$333,048
														Subtotal = $333,048

Issue Date FY: 2006 ( Subtotal = $342,996 )
2006	2006	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	4	5/31/2006	NON-COMPETING CONTINUATION	$342,996
														Subtotal = $342,996

Issue Date FY: 2005 ( Subtotal = $351,250 )
2005	2005	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	3	5/20/2005	NON-COMPETING CONTINUATION	$351,250
														Subtotal = $351,250

Issue Date FY: 2004 ( Subtotal = $351,250 )
2004	2004	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	2	5/26/2004	NON-COMPETING CONTINUATION	$351,250
														Subtotal = $351,250

Issue Date FY: 2003 ( Subtotal = $351,250 )
2003	2003	UNIVERSITY OF SOUTH DAKOTA	414 EAST CLARK STREET	VERMILLION	SD	57069	CLAY	USA	Cardiovascular Diseases Research	000	1	6/26/2003	NEW	$351,250
														Subtotal = $351,250

Grand Total All Awards = $6,909,227

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PKG and PKA Duo-Activation to Treat Cardiac Proteotoxicity

Award Number: R01HL072166

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2003

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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