Wednesday, April 9, 2025 4/9/2025

Novel Molecular Mechanisms Promote GPCR-Induced Bronchodilation in Asthma

Award Number: P01HL114471
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Novel Molecular Mechanisms Promote GPCR-Induced Bronchodilation in Asthma - Project Summary Our renewal of this interdisciplinary PPG remains focused on the theme of novel molecular mechanisms to inhibit human airway smooth muscle (HASM) contraction and promote bronchodilation within the context of airway inflammation and asthma. The principal hypothesis states that G protein coupled receptor (GPCR) desensitization and unbiased signaling limits the efficacy of conventional bronchodilators, such that targeting desensitization mechanisms, promoting biased agonism, circumventing mechanisms of ASM hypercontractility/airway hyperresponsiveness (AHR), or engaging novel bronchorelaxant mechanisms in HASM will provide superior therapy for asthma. Each Project addresses this hypothesis by either: 1) optimizing pro- relaxant signaling abilities of one of 3 different GPCRs using strategies rooted in cutting edge biophysical or pharmacological approaches; or 2) establishing novel intracellular targets mediating inflammation-driven AHR and increased GPCR pro-contractile signaling. Project 1 will establish the mechanisms by which TGF-β1 modulates excitation-contraction (EC) coupling of HASM and thereby identify novel therapeutic targets linked to both AHR and increased GPCR-mediated contraction. Project 2 will advance the recent discovery of bitter taste receptors (TAS2R) as novel bronchodilators clarifying the role of TAS2R subtypes in HASM, their mode of regulation and means to improve their efficacy through biased agonism. Project 3 will characterize the molecular basis of β2AR biased signaling to develop compounds that mediate Gs-biased signaling through either inhibition of β-arrestin interaction with the agonist-occupied β2AR (arrestin-biased negative allosteric modulators (NAMs)) or by enhancing coupling of the β2AR to Gs (biased orthosteric agonists). Project 4 will similarly characterize the mechanisms underlying biased signaling of OGR1, develop new biased OGR1 benzodiazepine derivatives with superior ability to bronchodilate, and determine the relative contribution of and mechanisms underlying peripheral benzodiazepine receptor activation by candidate drugs. The four projects will be supported by Core A that will use high through-put screening of small molecule libraries, whole genome, pooled shRNA libraries and virtual screening approaches to identify targets and effectors of bronchodilation. Core B will provide all de-identified human cell and tissue models to study novel mechanisms regulating EC coupling in HASM. Core C will provide administrative support for the program. The strengths of this Program are the common focus on a single theme and the productive working relationship among investigators with the ability to apply cutting edge GPCR biology to key questions in asthma biology and pharmacology.


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: 2023 ( Subtotal = $2,393,983 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Lung Diseases Research	006	10	8/17/2023	SUPPLEMENT FOR EXPANSION	$60,161
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Lung Diseases Research	005	10	8/16/2023	SUPPLEMENT FOR EXPANSION	$35,186
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Lung Diseases Research	004	10	8/15/2023	NON-COMPETING CONTINUATION	$2,298,636
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	003	8	2/6/2023	SUPPLEMENT FOR EXPANSION	-$55,918
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Lung Diseases Research	002	9	2/6/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$418,368
2023	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	000	8	2/6/2023	NON-COMPETING CONTINUATION	-$230,371
2023	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	001	8	2/6/2023	SUPPLEMENT FOR EXPANSION	-$132,079
														Subtotal = $2,393,983

Issue Date FY: 2022 ( Subtotal = $2,491,327 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	000	8	12/30/2021	SUPPLEMENT FOR EXPANSION	$55,918
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Lung Diseases Research	006	9	8/19/2022	SUPPLEMENT FOR EXPANSION	$76,612
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Lung Diseases Research	007	9	9/26/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Lung Diseases Research	005	9	8/18/2022	SUPPLEMENT FOR EXPANSION	$60,161
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	004	8	8/18/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Lung Diseases Research	002	9	8/12/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,298,636
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Lung Diseases Research	008	9	9/26/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	001	8	8/12/2022	NON-COMPETING CONTINUATION	$0
2022	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	003	8	8/18/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $2,491,327

Issue Date FY: 2021 ( Subtotal = $2,430,715 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	002	7	2/25/2021	SUPPLEMENT FOR EXPANSION	$55,467
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	003	8	8/9/2021	NON-COMPETING CONTINUATION	$2,298,636
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	004	8	8/10/2021	SUPPLEMENT FOR EXPANSION	$76,612
2021	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	001	6	2/23/2021	COMPETING CONTINUATION	$2,454
2021	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	000	5	2/23/2021	NON-COMPETING CONTINUATION	-$2,454
														Subtotal = $2,430,715

Issue Date FY: 2020 ( Subtotal = $2,290,948 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	000	7	8/13/2020	NON-COMPETING CONTINUATION	$2,290,948
														Subtotal = $2,290,948

Issue Date FY: 2019 ( Subtotal = $2,363,727 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	001	6	8/16/2019	COMPETING CONTINUATION	$2,363,727
2019	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	000	5	12/21/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,363,727

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	001	4	2/1/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$112
2018	2015	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	000	3	2/1/2018	NON-COMPETING CONTINUATION	-$112
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $2,435,478 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	004	5	7/30/2017	NON-COMPETING CONTINUATION	$2,435,478
2017	2016	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	001	4	11/1/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,926,966
2017	2016	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	003	4	6/14/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$287,158
2017	2015	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	000	3	11/1/2016	NON-COMPETING CONTINUATION	-$1,926,966
2017	2015	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	002	3	6/14/2017	NON-COMPETING CONTINUATION	$287,158
														Subtotal = $2,435,478

Issue Date FY: 2016 ( Subtotal = $2,435,478 )
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Lung Diseases Research	002	4	9/6/2016	SUPPLEMENT FOR EXPANSION	$59,528
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Lung Diseases Research	001	4	8/30/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,375,950
2016	2015	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	000	3	8/29/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,435,478

Issue Date FY: 2015 ( Subtotal = $2,353,263 )
2015	2015	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	000	3	8/8/2015	NON-COMPETING CONTINUATION	$2,353,263
														Subtotal = $2,353,263

Issue Date FY: 2014 ( Subtotal = $2,341,318 )
2014	2014	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	000	2	7/2/2014	NON-COMPETING CONTINUATION	$2,341,318
														Subtotal = $2,341,318

Issue Date FY: 2013 ( Subtotal = $2,365,675 )
2013	2013	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Lung Diseases Research	000	1	7/15/2013	NEW	$2,365,675
														Subtotal = $2,365,675

Grand Total All Awards = $23,901,912

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Novel Molecular Mechanisms Promote GPCR-Induced Bronchodilation in Asthma

Award Number: P01HL114471

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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