# Project 2: Contribution of a Non-Gastric Proton Pump to Airway Acidification, Respiratory Host Defense, and Lung Disease in Cystic Fibrosis

> **NIH NIH P01** · UNIVERSITY OF IOWA · 2022 · $333,775

## Abstract

PROJECT 2
PROJECT SUMMARY/ABSTRACT
Loss of the CFTR anion channel causes cystic fibrosis (CF), which is characterized by bacterial infection and
inflammation. To understand how CF disrupts airway defenses, we generated CF pigs and found that on the
day they are born, they have impaired respiratory host defenses. Within weeks, they spontaneously develop
hallmarks of CF airways: infection, inflammation, remodeling, mucus accumulation, and obstruction. Studies of
CF pigs revealed at least two respiratory host defense defects: reduced activity of antimicrobials in airway
surface liquid and impaired mucociliary transport. Both defects are caused, at least in part, by an abnormally
acidic airway liquid. Loss of CFTR-mediated bicarbonate secretion leaves unchecked acid secretion that
reduces pH. We found that a proton pump (ATP12A) is responsible for secreting acid into the airways. The
overarching goal of this project is to understand how ATP12A acid secretion impairs host defense and whether
the acidic pH causes CF lung disease. The project addresses three main questions. First, how is ATP12A
acid secretion regulated in CF airways? Understanding the control of ATP12A is important because varying
the rate of H+ secretion will change pH, which could exacerbate or attenuate disease severity. Second what is
the pH in the lumen of submucosal glands? Submucosal glands produce most of the airway mucus. Earlier
work showed that mucus emerging from CF submucosal glands ducts sometimes failed to break free from the
duct, which impaired mucociliary transport. Those discoveries and knowledge that an acidic pH increases
mucus elasticity make it imperative to know the pH in the submucosal gland lumen. This proposal develops
novel means to obtain that information. Third, does disrupting the ATP12A gene rescue CF defects? CF pigs
that have a disrupted ATP12A gene will allow a test of the hypotheses that preventing acid secretion will
increase pH in the submucosal gland lumen, improve mucociliary transport, and prevent CF lung disease. This
research will allow us to better understand how CF alters pH in the submucosal gland lumen and at the airway
surface, thereby disrupting respiratory host defenses. The knowledge of CF pathogenesis will accelerate
discovery of novel therapies and cures for this lethal disease.

## Key facts

- **NIH application ID:** 10470211
- **Project number:** 5P01HL091842-15
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** MICHAEL J. WELSH
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $333,775
- **Award type:** 5
- **Project period:** 2008-09-05 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470211

## Citation

> US National Institutes of Health, RePORTER application 10470211, Project 2: Contribution of a Non-Gastric Proton Pump to Airway Acidification, Respiratory Host Defense, and Lung Disease in Cystic Fibrosis (5P01HL091842-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10470211. Licensed CC0.

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