# Role of disrupted ASL pH regulation in small airways in CF lung disease pathogenesis

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2021 · $553,359

## Abstract

PROJECT SUMMARY / ABSTRACT
Cystic fibrosis (CF) is a common genetic disease caused by a defect in the CF transmembrane conductance
regulator (CFTR). The pathogenesis of CF lung disease is unclear and controversial, at least partially due to
lack of studies in an appropriate CF animal model. In addition, most studies regarding the pathogenesis rely on
data from cultured human diseased large proximal airways, such as tracheal and bronchial tissue. However,
pathological and clinical data suggest that the disease is initiated in small airways with a diameter <2mm.
Iowa group has engineered pigs with deletion or mutation of CFTR. These pigs mimic human CF, including
development of spontaneous infections and obstruction of airways with mucus and inflammatory cells. This
model provides an unprecedented opportunity to investigate the pathogenesis of CF lung disease. Our
objective for this study is to investigate how loss of CFTR leads to host defense defects in CF small airway
epithelia and if viral vector mediated delivery of CFTR cDNA to CF small airways will rescue host defense
defects. Our overall hypothesis is that AAV4 mediated delivery of CFTR will correct ASL properties and restore
host defense function of small airway epithelium in CF. In Aim 1, we will use AAV4 to deliver CFTR cDNA in
cultured small airway epithelial cells from CF pigs and examine ASL properties including pH and viscosity and
bacterial killing abilities. In Aim 2, we will use human small airway epithelia from CF patients to test the
hypothesis. In Aim 3, we will examine the cellular tropism and efficiency of AAV4 mediated gene delivery to
small airway epithelium in live pigs and human lung explant. The proposed studies will lead to a better
understanding of the CFTR-mediated host defense mechanisms and illustrate a potentially important yet
previously underappreciated role of small airway epithelial cells in pathogenesis of CF lung disease.

## Key facts

- **NIH application ID:** 10209528
- **Project number:** 1R01HL153165-01A1
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** xiaopeng Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $553,359
- **Award type:** 1
- **Project period:** 2021-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10209528

## Citation

> US National Institutes of Health, RePORTER application 10209528, Role of disrupted ASL pH regulation in small airways in CF lung disease pathogenesis (1R01HL153165-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10209528. Licensed CC0.

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