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

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $527,787

## Abstract

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.

## Key facts

- **NIH application ID:** 10800804
- **Project number:** 5R01HL157269-04
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** John David Dickinson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $527,787
- **Award type:** 5
- **Project period:** 2021-04-23 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800804

## Citation

> US National Institutes of Health, RePORTER application 10800804, Autophagy-mediated mucin degradation is necessary for resolution of mucous metaplasia (5R01HL157269-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10800804. Licensed CC0.

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