# Project 3: Contribution of Small Airways to Cystic Fibrosis Lung Disease Pathogenesis

> **NIH NIH P01** · UNIVERSITY OF IOWA · 2020 · $356,949

## Abstract

PROJECT 3
ABSTRACT
It is often assumed that CF lung disease begins in the small airways. While a number
of observations suggest this assumption is correct, we do not have direct experimental
evidence. Because we have more knowledge of host defense defects in large CF
airways, we might conjecture that the abnormalities in small CF airways are the same.
However, differences in epithelial morphology, cell types, and lack of submucosal
glands and continuous cartilages suggest that small airways are not simply “small”
large airways. The small airways have been relatively inaccessible for detailed
mechanistic studies. As a result, we lack answers to many key questions. What is
the airway surface liquid pH in CF small airways? How is it controlled? What
mechanism secretes protons into small airways? Is mucociliary transport disrupted in
small airways? Is the activity of ASL antimicrobials impaired? Is CFTR in small airways
sufficient to prevent CF lung disease? As CF lung disease progresses how do host
defenses and disease in small airways change? Our overarching hypothesis is that
lack of CFTR in the small airway is pivotal for the pathogenesis of CF lung disease.
We will investigate 3 specific aims:
Specific Aim 1. Does lack of CFTR in small airways result in host defense defects?
Based on our preliminary data we hypothesize that newborn CF small airways will be
more acidic, and will have an impairment in host defenses.
Specific Aim 2. Does V-ATPase play a role in regulating small airways airway surface
liquid pH? We hypothesize that V-ATPase is expressed on the apical surface of a
specific cell type of small airway epithelial cells and plays a role in a feedback
mechanism that regulates ASL pH.
Specific Aim 3. Will CFTR expression in small airways of prevent CF pig lung
disease? We will use a novel AAV vector to selectively express CFTR in the small
airway epithelial cells of CF pigs. We will investigate the effect of restoration of CFTR
function on manifestations of early lung.
Answers to these questions, will guide the field in understanding the contribution of
small airways to disease and in identifying strategies for better treatments of CF.

## Key facts

- **NIH application ID:** 9985174
- **Project number:** 5P01HL091842-13
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Joseph Zabner
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $356,949
- **Award type:** 5
- **Project period:** 2008-09-05 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985174

## Citation

> US National Institutes of Health, RePORTER application 9985174, Project 3: Contribution of Small Airways to Cystic Fibrosis Lung Disease Pathogenesis (5P01HL091842-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9985174. Licensed CC0.

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