# Epithelial progenitor cell dysfunction in fibrotic lung disease

> **NIH NIH P01** · CEDARS-SINAI MEDICAL CENTER · 2021 · $432,594

## Abstract

ABSTRACT
Fibrotic lung diseases including usual interstitial pneumonia/idiopathic pulmonary fibrosis (IPF) and chronic lung
allograft dysfunction (CLAD) are associated with defects in epithelial maintenance and repair that lead to
irreversible declines in lung function and death. However, little is known of mechanisms leading to defective
epithelial maintenance and remodeling in lung tissue of these patients. Over the previous funding period we
demonstrated that loss of alveolar type 2 (AT2) cells in lung tissue of patients with end-stage IPF is associated
with distal airway basal and secretory cell hyperplasia. Using state-of-the-art 3D culture models and genomics
approaches we found that alveolar epithelial progenitor (AT2) cells from lungs of IPF patients have reduced
colony-forming and clonogenic potentials and accompanying upregulation of the p53 pathway. Alveolar
progenitor cell dysfunction in mouse models was found to be a potent regulator of small airway basal cell
expansion similar to that observed in lungs of IPF patients. Basal cell expansion could be activated by interleukin
22, a cytokine that was induced following alveolar injury and whose elevated abundance has been associated
with fibrotic lung disease. Goals of the present application are to determine cellular mechanisms that contribute
to either regeneration or remodeling and molecular pathways that guide cells along either of these pathways
with the long-term expectation that novel therapies can be developed to promote normal tissue repair and/or
block fibrosis. Our experimental plan will address the overarching hypothesis that p53-dependent alveolar
progenitor cell dysfunction drives airway and parenchymal remodeling through a mechanism involving
IL23-mediated innate immune stimulation and elevated IL22 production. This hypothesis will be tested in
two aims that will define roles for p53 signaling in regulation of alveolar progenitor cells and define roles for IL22
in the regulation of basal cell expansion and recruitment to regions of alveolar injury. Completion of aims will
yield novel insights into the molecular regulation of airway epithelial progenitor cells that will guide development
of new therapies to treat patients with chronic lung disease.

## Key facts

- **NIH application ID:** 10198012
- **Project number:** 5P01HL108793-09
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Barry R Stripp
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $432,594
- **Award type:** 5
- **Project period:** 2012-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198012

## Citation

> US National Institutes of Health, RePORTER application 10198012, Epithelial progenitor cell dysfunction in fibrotic lung disease (5P01HL108793-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10198012. Licensed CC0.

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