# Mucin Disulfide Links as a Mechanism of Pathologic Mucus in Airway Disease

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $328,322

## Abstract

Project Summary
We have investigated the mechanisms of highly elastic airway mucus in cystic fibrosis and uncovered a
mechanism of mucus pathology that we propose as ubiquitous in multiple mucus-associated lung diseases and
a basis for the rational design of a novel mucolytic therapy. Specifically, we have discovered that mucus
elasticity in CF is a function of neutrophil oxidative stress that cross-links mucin polymers to stiffen the mucus
gel. We propose that other forms of oxidative stress - including eosinophil effects on mucins that are mediated
by eosinophil peroxidase (EPO) - will also stiffen airway mucus gels to slow mucus clearance and promote
airflow obstruction from mucus plugging. Our hypothesis leads to a rational approach for the design of novel
mucolytic drugs based on cleavage of mucin disulfide cross-links by thiol-saccharide compounds. We are
excited to collaborate with Dr. Oscarson in Project 1 and Dr. Lee in Project 3 to progress a thiol-saccharide
therapeutic to the clinic as a novel mucolytic for CF and later for asthma as well. We have three Aims. Aim 1
will collaborate with Project 1 to screen the mucolytic efficacy of thiol-saccharides compounds. Aim 2 will
explore how type 2 inflammation promotes intraluminal mucus accumulation in asthma - it will specifically
explore how EPO oxidized mucins to stiffen the airway mucus gel in asthma. Aim 3 will use CT lung imaging to
identify an asthma subgroup with the “asthma mucus phenotype” and determine they benefit from mucolytic
treatment with N-Acetyl Cysteine (NAC). This NAC study will provide proof of concept for later studies of the
efficacy of thiol-saccharide treatment for asthma.

## Key facts

- **NIH application ID:** 9990848
- **Project number:** 5P01HL128191-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** John V Fahy
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $328,322
- **Award type:** 5
- **Project period:** 2016-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990848

## Citation

> US National Institutes of Health, RePORTER application 9990848, Mucin Disulfide Links as a Mechanism of Pathologic Mucus in Airway Disease (5P01HL128191-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9990848. Licensed CC0.

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