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Molecular Regulation of Cardiovascular 7 TM Receptors

Award Number: R01HL016037
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/1976
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Molecular Regulation of Cardiovascular 7 TM Receptors - PROJECT SUMMARY/ABSTRACT MOLECULAR REGULATION OF CARDIOVASCULAR SEVEN TRANSMEMBRANE RECEPTORS. All aspects of cardiovascular function are regulated by members of the seven transmembrane receptor (7TMR or GPCR) family, and they are the commonest target of therapeutic drugs. A universal mechanism regulating these receptors is desensitization of heterotrimeric G protein signaling. Classically, this is mediated by a two-step process in which activated receptors are phosphorylated by G protein-coupled receptor kinases, leading to the binding of a β-arrestin (βarr) molecule which sterically interdicts further activation of the G protein. More recently it has become clear that βarrs can also serve as multifunctional adaptors which act as signal transducers in their own right. Moreover, for many receptors, ligands can be found which disproportionately activate either G protein- or βarr-mediated signaling—i.e., biased ligands which may possess greater specificity of action and fewer side effects. Biased drugs for GPCR's represent a major, as yet largely unmined opportunity for drug development. Another such untapped opportunity to develop drugs with greater specificity and safety is presented by allosteric ligands which, rather than binding to the orthosteric site of the receptors, where endogenous ligands bind, interact with other sites. Accordingly, this proposal has three closely linked aims which involve laying the groundwork for targeting both of these largely untapped opportunities by developing the first biased allosteric ligands for a receptor of great cardiovascular significance, the angiotensin II type I receptor (AT1R) as well as for the βarrs. In the process we aim to also develop a molecular and atomic level understanding of how biased allosteric GPCR drugs regulate signaling. These aims are: 1. To discover the first small molecule biased allosteric modulators of the AT1R; 2. To discover novel small molecule allosteric modulators of the signal transducer βarr; 3. To elucidate the mechanisms of allosteric regulation of downstream effectors of βarrs. The insights which we will generate have the potential to guide the design of powerful new cardiovascular drugs and will further our understanding of the conserved signaling mechanisms of the greater GPCR family.


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 = $703,084 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cardiovascular Diseases Research	000	53	5/21/2025	NON-COMPETING CONTINUATION	$703,084
														Subtotal = $703,084

Issue Date FY: 2024 ( Subtotal = $705,383 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cardiovascular Diseases Research	004	52	6/25/2024	NON-COMPETING CONTINUATION	$57,582
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cardiovascular Diseases Research	001	52	4/19/2024	NON-COMPETING CONTINUATION	$647,801
2024	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cardiovascular Diseases Research	003	51	5/2/2024	COMPETING CONTINUATION	$411,391
2024	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cardiovascular Diseases Research	000	51	2/7/2024	COMPETING CONTINUATION	$0
2024	2022	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cardiovascular Diseases Research	002	50	5/2/2024	NON-COMPETING CONTINUATION	-$411,391
														Subtotal = $705,383

Issue Date FY: 2023 ( Subtotal = $736,195 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cardiovascular Diseases Research	000	51	7/21/2023	COMPETING CONTINUATION	$736,195
														Subtotal = $736,195

Issue Date FY: 2022 ( Subtotal = $776,537 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	50	6/5/2022	NON-COMPETING CONTINUATION	$776,537
														Subtotal = $776,537

Issue Date FY: 2021 ( Subtotal = $784,482 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	49	7/8/2021	NON-COMPETING CONTINUATION	$784,482
														Subtotal = $784,482

Issue Date FY: 2020 ( Subtotal = $793,762 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	002	48	6/20/2020	NON-COMPETING CONTINUATION	$793,762
2020	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	001	47	2/25/2020	COMPETING CONTINUATION	$339,492
2020	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	46	2/25/2020	NON-COMPETING CONTINUATION	-$339,492
														Subtotal = $793,762

Issue Date FY: 2019 ( Subtotal = $804,984 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	47	6/22/2019	COMPETING CONTINUATION	$804,984
														Subtotal = $804,984

Issue Date FY: 2018 ( Subtotal = $606,456 )
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	46	8/3/2018	NON-COMPETING CONTINUATION	$606,456
														Subtotal = $606,456

Issue Date FY: 2017 ( Subtotal = $604,566 )
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	45	7/3/2017	NON-COMPETING CONTINUATION	$437,565
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	001	45	9/13/2017	SUPPLEMENT FOR EXPANSION	$167,001
														Subtotal = $604,566

Issue Date FY: 2016 ( Subtotal = $435,732 )
2016	2016	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	44	7/12/2016	NON-COMPETING CONTINUATION	$435,732
														Subtotal = $435,732

Issue Date FY: 2015 ( Subtotal = $478,655 )
2015	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	43	7/30/2015	COMPETING CONTINUATION	$478,655
														Subtotal = $478,655

Issue Date FY: 2014 ( Subtotal = $460,439 )
2014	2014	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	42	6/27/2014	NON-COMPETING CONTINUATION	$460,439
														Subtotal = $460,439

Issue Date FY: 2013 ( Subtotal = $447,284 )
2013	2013	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	41	7/2/2013	NON-COMPETING CONTINUATION	$447,284
														Subtotal = $447,284

Issue Date FY: 2012 ( Subtotal = $469,835 )
2012	2012	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	40	7/30/2012	NON-COMPETING CONTINUATION	$469,835
														Subtotal = $469,835

Issue Date FY: 2011 ( Subtotal = $469,835 )
2011	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	39	7/8/2011	NON-COMPETING CONTINUATION	$469,835
														Subtotal = $469,835

Issue Date FY: 2010 ( Subtotal = $474,580 )
2010	2010	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	001	38	6/24/2010	COMPETING CONTINUATION	$474,580
2010	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	37	6/23/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $474,580

Issue Date FY: 2009 ( Subtotal = $457,823 )
2009	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	37	7/15/2009	NON-COMPETING CONTINUATION	$457,823
														Subtotal = $457,823

Issue Date FY: 2008 ( Subtotal = $435,598 )
2008	2008	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	36	8/18/2008	NON-COMPETING CONTINUATION	$435,598
														Subtotal = $435,598

Issue Date FY: 2007 ( Subtotal = $430,158 )
2007	2007	DUKE UNIVERSITY	BOX 104135	DURHAM	NC	27708	DURHAM	USA	Cardiovascular Diseases Research	000	35	8/20/2007	NON-COMPETING CONTINUATION	$430,158
														Subtotal = $430,158

Issue Date FY: 2006 ( Subtotal = $430,105 )
2006	2006	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Cardiovascular Diseases Research	000	34	8/21/2006	NON-COMPETING CONTINUATION	$430,105
														Subtotal = $430,105

Issue Date FY: 2005 ( Subtotal = $435,000 )
2005	2005	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Cardiovascular Diseases Research	000	33	7/1/2005	COMPETING CONTINUATION	$435,000
														Subtotal = $435,000

Grand Total All Awards = $14,445,774

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Molecular Regulation of Cardiovascular 7 TM Receptors

Award Number: R01HL016037

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/1976

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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