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Mechanisms of Maladaptation in Heart Failure

Award Number: R01HL056687
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/1996
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Mechanisms of Maladaptation in Heart Failure - Summary of Work G protein-coupled receptors (GPCRs) are one of the largest group of therapeutic targets in cardiovascular disease. Ligands for GPCRs are characterized as agonists: those that stabilize a receptor conformation that promote activation of heterotrimeric G-proteins to generate second-messenger signaling; or antagonists such as β-blockers that block such activation. While β-blockers are standard of therapy in heart failure, there is evidence for a positive relationship between higher β-blocker dose and improved clinical outcomes. However, achieving a maximal dose is often difficult due to the development of intolerable adverse effects. Thus developing novel ligands that have improved efficacy and reduced untoward effects is a huge unmet need. Studies over the past 2 decades, in a large part from investigators on this proposal, have shown that orthosteric ligands, i.e. the binding site of the endogenous ligand, stabilize distinct active receptor conformations to selectively engage either G-protein or β-arrestin, to induce distinct signaling pathways. This concept of orthosteric ligand-dependent transducer selectivity is known as biased signaling and has been shown to activate cardioprotective pathways. While the majority of GPCR ligands target orthosteric binding sites, an emerging area of receptor biology and drug development is the identification of ligands that bind to allosteric, or topographically distinct, sites on receptors. Allosteric ligands that potentiate activity of orthosteric agonists are termed positive allosteric modulators (PAMs), while those that noncompetitively decrease the activity of orthosteric agonists are termed negative allosteric modulators (NAMs). It is now apparent that allosteric ligands may offer great benefit as therapeutics because of enhanced receptor specificity and efficacy. The objective of this R01 renewal is to identify, characterize, and translate newly identified allosteric modulators on the β1 adrenergic receptor (β1AR) from our recently performed DNA- encoded library (DEL) screen of 1 billion unique chemical entities with the ultimate goal of identifying β-arrestin biased PAMs. To accomplish this ambitious goal, I have assembled a team of experts in GPCR biology and organic chemistry that are known for innovative, paradigm-shifting research. I propose the following specific aims.


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 = $769,926 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cardiovascular Diseases Research	001	28	7/9/2025	NON-COMPETING CONTINUATION	$76,993
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cardiovascular Diseases Research	000	28	4/8/2025	NON-COMPETING CONTINUATION	$692,933
														Subtotal = $769,926

Issue Date FY: 2024 ( Subtotal = $754,528 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cardiovascular Diseases Research	000	27	6/11/2024	NON-COMPETING CONTINUATION	$754,528
2024	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cardiovascular Diseases Research	002	26	6/13/2024	COMPETING CONTINUATION	$59,965
2024	2022	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cardiovascular Diseases Research	001	25	6/13/2024	NON-COMPETING CONTINUATION	-$59,965
														Subtotal = $754,528

Issue Date FY: 2023 ( Subtotal = $769,926 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cardiovascular Diseases Research	000	26	7/17/2023	COMPETING CONTINUATION	$769,926
														Subtotal = $769,926

Issue Date FY: 2022 ( Subtotal = $731,175 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	25	7/8/2022	NON-COMPETING CONTINUATION	$731,175
														Subtotal = $731,175

Issue Date FY: 2021 ( Subtotal = $744,055 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	24	6/29/2021	NON-COMPETING CONTINUATION	$744,055
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	001	24	8/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $744,055

Issue Date FY: 2020 ( Subtotal = $756,935 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	002	23	8/27/2020	NON-COMPETING CONTINUATION	$756,935
2020	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	001	22	2/25/2020	COMPETING CONTINUATION	$1,052
2020	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	21	2/25/2020	NON-COMPETING CONTINUATION	-$1,052
														Subtotal = $756,935

Issue Date FY: 2019 ( Subtotal = $786,675 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	002	22	7/9/2019	COMPETING CONTINUATION	$786,675
2019	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	001	21	7/8/2019	NON-COMPETING CONTINUATION	$0
2019	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	21	6/20/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $786,675

Issue Date FY: 2018 ( Subtotal = $397,500 )
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	21	4/27/2018	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2017 ( Subtotal = $397,500 )
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	20	4/9/2017	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2016 ( Subtotal = $397,500 )
2016	2016	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	19	4/5/2016	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2015 ( Subtotal = $397,500 )
2015	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	18	7/5/2015	COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2014 ( Subtotal = $384,650 )
2014	2014	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	17	4/16/2014	NON-COMPETING CONTINUATION	$384,650
														Subtotal = $384,650

Issue Date FY: 2013 ( Subtotal = $373,660 )
2013	2013	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	16	6/11/2013	NON-COMPETING CONTINUATION	$373,660
														Subtotal = $373,660

Issue Date FY: 2012 ( Subtotal = $392,500 )
2012	2012	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	15	5/14/2012	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2011 ( Subtotal = $392,500 )
2011	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	001	14	8/17/2011	COMPETING CONTINUATION	$392,500
2011	2010	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	13	8/17/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $392,500

Issue Date FY: 2010 ( Subtotal = $376,263 )
2010	2010	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	13	1/20/2010	NON-COMPETING CONTINUATION	$376,263
														Subtotal = $376,263

Issue Date FY: 2009 ( Subtotal = $376,263 )
2009	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	12	1/22/2009	NON-COMPETING CONTINUATION	$376,263
														Subtotal = $376,263

Issue Date FY: 2008 ( Subtotal = $376,263 )
2008	2008	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	11	2/5/2008	NON-COMPETING CONTINUATION	$376,263
														Subtotal = $376,263

Issue Date FY: 2007 ( Subtotal = $376,263 )
2007	2007	DUKE UNIVERSITY	BOX 104135	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	10	4/30/2007	NON-COMPETING CONTINUATION	$376,263
														Subtotal = $376,263

Issue Date FY: 2006 ( Subtotal = $385,000 )
2006	2006	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Cardiovascular Diseases Research	000	9	1/24/2006	COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2003 ( Subtotal = $308,000 ) (Continued on the next page)
Grand Total All Awards = $11,975,830

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Mechanisms of Maladaptation in Heart Failure

Award Number: R01HL056687

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/1996

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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