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Airway Inflammatory Pathways Regulating Glucocorticoid Receptor Phosphorylation

Award Number: R01HL111541
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2012
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Airway Inflammatory Pathways Regulating Glucocorticoid Receptor Phosphorylation - PROJECT SUMMARY Increased airway smooth muscle (ASM) mass, a major feature of airway remodeling in asthma, profoundly contributes to asthma morbidity, mortality, and pathogenesis. This increased mass is due in large part to enhanced proliferative activity of ASM cells. Unfortunately, proliferation of these latter cells is unaffected by current asthma medications, as the process appears to be insensitive to glucocorticoid (GC) effects. While research aimed at understanding the basis of GC insensitivity (GCI) has focused on the role of immune cells, few investigators have studied GCI in ASM cells, the pivotal cell regulating bronchomotor tone. The long-term goal of this research is to identify factors that impair the sensitivity of the ASM proliferative response to GC in patients with asthma, with the ultimately goal of establishing therapeutic strategies to circumvent GCI. The current proposal will examine the cellular and molecular mechanisms by which growth factors (GFs) modulate ASM sensitivity to GCs. Using unique cellular models of ASM cells derived from patients with asthma, our exciting preliminary data supports the central hypothesis that GF-induced abnormal site-specific phosphorylation of glucocorticoid receptor (GR) impairs ASM sensitivity to GC. These data now suggest that (previously unappreciated) GR phosphorylation at serine 134 (ser134) residue inhibits GR signaling. These data also suggest that GF-induced activation of serine/threonine kinase protein kinase B (PKB/Akt) and serine/threonine protein phosphatase 2A (PP2A) regulates GR-ser134 phosphorylation. The rationale for the proposed research is that understanding the interplay among GR signaling and GF-induced kinases and/or phosphatases may uncover critical information for the development of novel therapeutics to overcome GCI in asthma. Our hypotheses will be tested by pursuing four specific aims: to identify the functional consequences of GF-induced abnormal GR site-specific phosphorylation on GR signaling (Aim 1); to characterize the contribution of kinases and phosphatases to GF-induced abnormal GR site-specific phosphorylation (Aim 2); and to elucidate the role of steroid-target genes in modulating GC anti-proliferative effects in ASM cells (Aim 3). To this end, we generated tools (antibody, mutated constructs) to examine the role of GR-ser134 phosphorylation. In all aims, pharmacological inhibitors, mutated constructs, siRNA, and expression vectors will be used to modulate the expression of steroid co-repressor, kinases, phosphatases, and steroid-target genes, after which GR site-specific phosphorylation, GR-mediated transactivation activities and sub-cellular localization, and ASM growth will be analyzed using state-of-the-art approaches already established in our laboratories. We will also determine the clinical significance of our in vitro observations by examining whether the aforementioned pathways are activated in tissues using endobronchial biopsies from subjects both with and without asthma (Aim 4). This integrated translational approach is expected to advance our understanding of the mechanisms that contribute to the development of GCI in some patients with asthma.


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	2021	ROWAN UNIVERSITY	201 MULLICA HILL RD	GLASSBORO	NJ	08028	GLOUCESTER	USA	Lung Diseases Research	000	12	5/13/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	LONG ISLAND UNIVERSITY	700 NORTHERN BLVD	GREENVALE	NY	11548	NASSAU	USA	Lung Diseases Research	000	11	11/3/2022	NON-COMPETING CONTINUATION	-$271,121
2023	2021	ROWAN UNIVERSITY	201 MULLICA HILL RD RT 322	GLASSBORO	NJ	08028	GLOUCESTER	USA	Lung Diseases Research	001	12	11/4/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$271,121
2023	2021	LONG ISLAND UNIVERSITY	700 NORTHERN BLVD	GREENVALE	NY	11548	NASSAU	USA	Lung Diseases Research	003	11	1/30/2023	NON-COMPETING CONTINUATION	-$92,716
2023	2021	ROWAN UNIVERSITY	201 MULLICA HILL RD	GLASSBORO	NJ	08028	GLOUCESTER	USA	Lung Diseases Research	004	12	1/30/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$300,155
2023	2020	LONG ISLAND UNIVERSITY	700 NORTHERN BLVD	GREENVALE	NY	11548	NASSAU	USA	Lung Diseases Research	002	10	1/30/2023	NON-COMPETING CONTINUATION	-$207,439
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	LONG ISLAND UNIVERSITY	700 NORTHERN BLVD	GREENVALE	NY	11548	NASSAU	USA	Lung Diseases Research	000	11	9/1/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $363,837 )
2021	2021	LONG ISLAND UNIVERSITY	700 NORTHERN BLVD	GREENVALE	NY	11548	NASSAU	USA	Lung Diseases Research	000	11	5/14/2021	NON-COMPETING CONTINUATION	$363,837
														Subtotal = $363,837

Issue Date FY: 2020 ( Subtotal = $362,224 )
2020	2020	LONG ISLAND UNIVERSITY	700 NORTHERN BLVD	GREENVALE	NY	11548	NASSAU	USA	Lung Diseases Research	000	10	5/6/2020	NON-COMPETING CONTINUATION	$362,224
														Subtotal = $362,224

Issue Date FY: 2019 ( Subtotal = $345,789 )
2019	2019	LONG ISLAND UNIVERSITY	700 NORTHERN BLVD	GREENVALE	NY	11548	NASSAU	USA	Lung Diseases Research	004	9	5/15/2019	NON-COMPETING CONTINUATION	$345,789
2019	2018	LONG ISLAND UNIVERSITY	700 NORTHERN BLVD	GREENVALE	NY	11548	NASSAU	USA	Lung Diseases Research	003	8	5/6/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$16,911
2019	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	001	7	1/31/2019	COMPETING CONTINUATION	-$348,027
2019	2018	LONG ISLAND UNIVERSITY	700 NORTHERN BLVD	GREENVALE	NY	11548	NASSAU	USA	Lung Diseases Research	000	8	11/28/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$348,027
2019	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	002	7	5/6/2019	COMPETING CONTINUATION	-$16,911
														Subtotal = $345,789

Issue Date FY: 2018 ( Subtotal = $437,663 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	000	7	5/21/2018	COMPETING CONTINUATION	$437,663
2018	2016	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	001	6	6/29/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $437,663

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Lung Diseases Research	000	5	2/20/2017	EXTENSION WITH OR WITHOUT FUNDS	-$368,700
2017	2016	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	001	6	2/22/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$368,700
2017	2016	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Lung Diseases Research	003	5	2/27/2017	EXTENSION WITH OR WITHOUT FUNDS	-$20,095
2017	2016	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Lung Diseases Research	002	5	2/27/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
2017	2016	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Lung Diseases Research	004	6	2/27/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$20,095
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $368,700 )
2016	2016	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Lung Diseases Research	000	5	2/22/2016	EXTENSION WITH OR WITHOUT FUNDS	$368,700
														Subtotal = $368,700

Issue Date FY: 2015 ( Subtotal = $363,169 )
2015	2015	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Lung Diseases Research	000	4	2/24/2015	NON-COMPETING CONTINUATION	$363,169
														Subtotal = $363,169

Issue Date FY: 2014 ( Subtotal = $361,326 )
2014	2014	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Lung Diseases Research	000	3	2/25/2014	NON-COMPETING CONTINUATION	$361,326
														Subtotal = $361,326

Issue Date FY: 2013 ( Subtotal = $351,002 )
2013	2013	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Lung Diseases Research	000	2	2/21/2013	NON-COMPETING CONTINUATION	$331,830
2013	2013	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Lung Diseases Research	001	2	7/30/2013	NON-COMPETING CONTINUATION	$19,172
														Subtotal = $351,002

Issue Date FY: 2012 ( Subtotal = $382,450 )
2012	2012	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Lung Diseases Research	001	1	2/27/2012	NEW	$0
2012	2012	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Lung Diseases Research	000	1	2/15/2012	NEW	$382,450
														Subtotal = $382,450

Grand Total All Awards = $3,336,160

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Airway Inflammatory Pathways Regulating Glucocorticoid Receptor Phosphorylation

Award Number: R01HL111541

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2012

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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