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Immune-driven Airway Epithelial Dysfunction in Muco-obstructive Asthma

Award Number: U19AI077439
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2008
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Immune-driven Airway Epithelial Dysfunction in Muco-obstructive Asthma - OVERALL SUMMARY This proposal seeks continued support for the UCSF Asthma and Allergic Diseases Cooperative Research Center’s longstanding and productive efforts to understand how type 2 immune responses in the airway act on epithelial cells to produce muco-obstructive pathology, a central feature of severe asthma and a major contributor to fatality from this disease. Our Center has made major contributions to identifying type 2 high asthma as the major asthma endotype, demonstrating that the type 2 cytokine IL-13 acts directly on airway epithelial cells to induce pathological changes in mucus, and showing that mucus plugging is a persistent feature of asthma that is associated with type 2 responses and with increased asthma severity. The overall objective of this proposal is to understand molecular mechanisms that account for alterations in secretory cell and mucus function that are important in severe asthma. The overarching hypothesis that serves as the focus of this renewal is that local type 2 immune responses induce IL-13-mediated changes in epithelial gene expression and that these changes, which involve several novel molecular mechanisms not previously explored, alter differentiation of secretory cells and production and secretion of mucins, leading to mucus plugging and airway obstruction. The proposal includes two highly related projects, each of which focuses on molecules and pathways that have previously unknown roles in secretory cell biology and mucus dysfunction. Project 1 will determine the roles of the tetraspanin TSPAN8, which we recently found to be required for stimulated release of MUC5AC, the major component of mucus plugs, and investigate the contributions of cysteine proteases and cystatin inhibitors implicated in our preliminary studies of mucociliary clearance in IL-13-stimulated primary human bronchial epithelial cells (HBECs). In addition, project 1 will directly assess the relationships between type 2 immune responses, epithelial alterations, and mucus plugging by analyzing lung tissue and HBECs from individuals with asthma and controls. Project 2 focuses on understanding new findings showing key roles for airway epithelial miRNAs in the miR-141/200 family and particular portions of the ER stress response in secretory cell differentiation, pathologic mucus production, and mucus plugging in asthma. Every aim of both projects depends upon a Clinical Subject and Biospecimen Processing and Analysis Core that will study banked lung specimens (for detailed molecular studies of mucus plugs, including from fatal asthma), conduct a new bronchoscopy-based study to obtain freshly isolated cells, provide banked human bronchial epithelial cells, and store, analyze, and disseminate data. The Administrative Core will coordinate our Center and our interactions with other AADCRCs and NIAID. The proposed studies will provide new mechanistic insights that are highly relevant to the pathogenesis of severe asthma and may lead to novel therapeutic targets that address unmet needs.


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: 2026 ( Subtotal = $1,410,836 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	19	4/9/2026	NON-COMPETING CONTINUATION	$1,410,836
														Subtotal = $1,410,836

Issue Date FY: 2025 ( Subtotal = $1,470,038 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	004	18	8/15/2025	SUPPLEMENT FOR EXPANSION	$86,339
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	002	18	4/29/2025	NON-COMPETING CONTINUATION	$1,401,080
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	003	17	7/11/2025	OTHER REVISION	$0
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	17	4/21/2025	TERMINATION	$0
2025	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	14	4/8/2025	SUPPLEMENT FOR EXPANSION	-$17,381
														Subtotal = $1,470,038

Issue Date FY: 2024 ( Subtotal = $1,456,627 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	003	17	8/15/2024	SUPPLEMENT FOR EXPANSION	$48,434
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	002	17	3/25/2024	NON-COMPETING CONTINUATION	$1,408,193
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	16	1/3/2024	COMPETING CONTINUATION	$10,470
2024	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	15	1/3/2024	NON-COMPETING CONTINUATION	-$10,470
														Subtotal = $1,456,627

Issue Date FY: 2023 ( Subtotal = $1,437,786 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	16	3/15/2023	COMPETING CONTINUATION	$1,437,786
2023	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	14	3/7/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $1,437,786

Issue Date FY: 2022 ( Subtotal = $1,361,965 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	002	15	4/13/2022	NON-COMPETING CONTINUATION	$1,361,965
2022	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	14	4/4/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	14	4/4/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $1,361,965

Issue Date FY: 2021 ( Subtotal = $4,836,200 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	002	14	3/24/2021	SUPPLEMENT FOR EXPANSION	$551,676
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	14	3/23/2021	SUPPLEMENT FOR EXPANSION	$2,888,226
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	14	3/12/2021	NON-COMPETING CONTINUATION	$1,396,298
														Subtotal = $4,836,200

Issue Date FY: 2020 ( Subtotal = $8,271,822 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	13	3/27/2020	NON-COMPETING CONTINUATION	$1,411,690
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	002	13	5/11/2020	SUPPLEMENT FOR EXPANSION	$5,742,559
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	004	13	5/13/2020	SUPPLEMENT FOR EXPANSION	$5,742,559
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	003	13	5/12/2020	SUPPLEMENT FOR EXPANSION	-$5,742,559
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	13	5/8/2020	SUPPLEMENT FOR EXPANSION	$1,117,573
														Subtotal = $8,271,822

Issue Date FY: 2019 ( Subtotal = $1,412,120 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	12	9/9/2019	NON-COMPETING CONTINUATION	$0
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	12	3/27/2019	NON-COMPETING CONTINUATION	$1,412,120
														Subtotal = $1,412,120

Issue Date FY: 2018 ( Subtotal = $1,428,013 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	11	1/31/2018	COMPETING CONTINUATION	$1,415,888
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	11	2/5/2018	COMPETING CONTINUATION	$12,125
2018	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	002	10	8/8/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,428,013

Issue Date FY: 2017 ( Subtotal = $1,521,253 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	10	3/20/2017	NON-COMPETING CONTINUATION	$1,521,253
														Subtotal = $1,521,253

Issue Date FY: 2016 ( Subtotal = $1,579,126 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	9	3/15/2016	EXTENSION WITH OR WITHOUT FUNDS	$1,579,126
														Subtotal = $1,579,126

Issue Date FY: 2015 ( Subtotal = $1,579,126 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	8	3/16/2015	NON-COMPETING CONTINUATION	$1,579,126
														Subtotal = $1,579,126

Issue Date FY: 2014 ( Subtotal = $1,680,602 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	7	3/21/2014	NON-COMPETING CONTINUATION	$1,680,602
														Subtotal = $1,680,602

Issue Date FY: 2013 ( Subtotal = $1,644,802 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	6	1/25/2013	COMPETING CONTINUATION	$1,644,802
														Subtotal = $1,644,802

Issue Date FY: 2012 ( Subtotal = $1,556,802 )
2012	2012	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	5	3/30/2012	NON-COMPETING CONTINUATION	$1,556,802
														Subtotal = $1,556,802

Issue Date FY: 2011 ( Subtotal = $1,546,847 ) (Continued on the next page)
Grand Total All Awards = $39,643,025

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Immune-driven Airway Epithelial Dysfunction in Muco-obstructive Asthma

Award Number: U19AI077439

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 04/01/2008

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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