# Project 1: Mucociliary Transport in Cystic Fibrosis Lung Disease

> **NIH NIH P01** · UNIVERSITY OF IOWA · 2022 · $371,812

## Abstract

PROJECT 1
PROJECT SUMMARY
Despite the development of new therapies, cystic fibrosis (CF) remains a life-shortening disease. Early
interventions aimed at correcting the initial host defense defects and preventing/reducing infection and mucus
accumulation could dramatically improve the course of CF lung disease. It is widely known that mutations in
the gene encoding the HCO3- and Cl--conducting channel CFTR cause CF; in spite of this knowledge, lack of
an animal model that replicates human CF has obscured the origins of disease. CF pigs provided us with the
unprecedented opportunity to investigate the CF lung at very early time points. At birth, CF pigs lack airway
disease, but within weeks of birth CF pigs spontaneously develop hallmark features of CF lung disease
including airway inflammation, infection, mucus accumulation, and remodeling. We previously found that CF
pigs have at least two host defense defects on the day that they are born: a) reduced activity of airway surface
liquid antimicrobials; and b) defective mucociliary transport (MCT) following cholinergic stimulation, which
elicits copious mucus secretion from submucosal glands. Recent mechanistic investigations revealed that CF
submucosal glands secrete strands of mucus that sometimes do not break free after emerging onto the airway
surface. Instead, they remain attached to the gland ducts, hindering MCT. These findings directly link
impaired MCT to loss of anion transport, indicating that defective MCT is a primary abnormality. Our central
hypothesis is that loss of CFTR causes MCT defects that contribute to early CF airway disease. Thus, there is
a critical need to better understand the underlying mechanism for MCT defects, whether these defects are
impacted by disease progression, and how they might be corrected. In a new direction for this project, we
focus our studies on the mucus strands that fail to detach from the CF submucosal gland duct and concentrate
our efforts towards determining if this defect is correctable. We will investigate the following Specific Aims: (1)
Which factors impact mucus strand formation, breakage, and clearance? Our working hypothesis is that
altering the chemical environment into which mucus strands are formed and released will impact strand
breakage and clearance. (2) In CF airways, does inducing release of mucus strands from submucosal gland
ducts restore MCT? We postulate that releasing stuck mucus strands will reverse MCT defects, thereby
enhancing MCT in CF. (3) How does early CF disease progression and viral infection impact MCT? CF pigs
have host defense defects present at birth and within weeks of age develop airway disease. Here we will
discover how early infection, inflammation, and mucus accumulation affect MCT in CF pigs. By focusing on
the pathogenesis of early CF airway disease, we hope to accelerate discovery of new therapeutic interventions
and identify endpoints for early CF.

## Key facts

- **NIH application ID:** 10470210
- **Project number:** 5P01HL091842-15
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** DAVID A STOLTZ
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $371,812
- **Award type:** 5
- **Project period:** 2008-09-05 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470210

## Citation

> US National Institutes of Health, RePORTER application 10470210, Project 1: Mucociliary Transport in Cystic Fibrosis Lung Disease (5P01HL091842-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10470210. Licensed CC0.

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