Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Autophagy-mediated mucin degradation is necessary for resolution of mucous metaplasia

Award Number: R01HL157269
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/23/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2027

Group Awards By:

View Award Description

Autophagy-mediated mucin degradation is necessary for resolution of mucous metaplasia - Muco-obstructive airway diseases including asthma, COPD, cystic fibrosis, and non-CF bronchiectasis have diverse genetic and environmental origins, but have certain common features that includes pathologic epithelial changes referred to as mucous metaplasia. Airway secretory cells differentiate into mucous cells with a goblet cell morphology packed with mucin granules containing MUC5AC and, to lesser extent, MUC5B. These airway diseases are characterized by frequent exacerbations due to mucous hypersecretion and blockage of the airways that leads to loss of lung function, hospitalization, and risk of death. While many of the factors that cause mucous metaplasia have been identified, little is known about how it resolves. Autophagy is a key cellular protein recycling system that degrades proteins in response to nutrient deprivation, inflammation, and infection. We have spent the last several years studying the role of autophagy in airway disease using models with genetic deletions of a key autophagy regulatory genes. In this application, we propose a new paradigm in which mucin granule degradation contributes to resolution of mucous metaplasia through the action of autophagy. Three key findings in our preliminary data support this hypothesis: First, autophagy deficient mouse and cell culture models accumulate more cytoplasmic mucin granules during mucous metaplasia and particularly during resolution. Second, mucous metaplasia is associated with mTOR activation and increased epithelial metabolism which is then down-regulate during resolution. We propose that this shift in metabolism is the key trigger initiating mucin degradation during resolution. Third, mimicking this shift in metabolism with mTOR inhibitors leads to autophagy activation and mucin degradation in human airway epithelial secretory cells. To test our hypothesis that autophagy leads to degradation of mucin granules, we propose three research aims: First, we will determine how mTOR signaling contributes to metabolism change in the secretory cell and ultimately to autophagy-mediated mucin degradation. Second, we will characterize the importance of autolysosome-lysosome fusion during mucous metaplasia resolution by examinig vesicle trafficking, lysosome biogenesis, and lysosome proteolytic function. Third, we will explore mucin degradation as a therapeutic strategy in models of muco-obstructive airway diseases. These findings can provide the framework for a new therapeutic strategy to hasten the resolution of airway disease exacerbations.


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 = $0 )
2026	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Lung Diseases Research	000	5	1/16/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $538,557 )
2025	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Lung Diseases Research	001	5	7/29/2025	NON-COMPETING CONTINUATION	$53,855
2025	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Lung Diseases Research	000	5	3/25/2025	NON-COMPETING CONTINUATION	$484,702
														Subtotal = $538,557

Issue Date FY: 2024 ( Subtotal = $527,787 )
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Lung Diseases Research	001	4	6/20/2024	NON-COMPETING CONTINUATION	$43,085
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Lung Diseases Research	000	4	3/27/2024	NON-COMPETING CONTINUATION	$484,702
														Subtotal = $527,787

Issue Date FY: 2023 ( Subtotal = $538,557 )
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Lung Diseases Research	000	3	3/3/2023	NON-COMPETING CONTINUATION	$538,557
														Subtotal = $538,557

Issue Date FY: 2022 ( Subtotal = $542,314 )
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Lung Diseases Research	001	2	6/14/2022	NON-COMPETING CONTINUATION	$54,236
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Lung Diseases Research	000	2	3/14/2022	NON-COMPETING CONTINUATION	$488,078
														Subtotal = $542,314

Issue Date FY: 2021 ( Subtotal = $557,406 )
2021	2021	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Lung Diseases Research	000	1	4/23/2021	NEW	$523,543
2021	2021	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Lung Diseases Research	001	1	7/31/2021	NEW	$33,863
														Subtotal = $557,406

Grand Total All Awards = $2,704,621

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Autophagy-mediated mucin degradation is necessary for resolution of mucous metaplasia

Award Number: R01HL157269

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/23/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer