# Mesenchymal modulation of epithelial metaplasia in lung fibrosis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $586,537

## Abstract

Project Summary/Abstract
Aberrant epithelial reprogramming can take the form of metaplasia, characterized by the appearance of
mature cell types that are not normally present at the site of injury. In organ fibrosis, this often culminates
in a transformed barrier composed of matrix-laden scars and metaplastic epithelium. A pathognomonic
feature of idiopathic pulmonary fibrosis (IPF) is the ectopic appearance of KRT5+ basal cells in the
damaged alveolar compartment, the presence of which correlates with disease severity and survival. This
suggests that metaplasia is a clinically relevant feature of lung fibrosis, and understanding this pathologic
form of epithelial plasticity could present potential therapeutic targets. We have previously shown that
hedgehog (Hh)-activated mesenchyme contributes to components of the scar in fibrotic repair. We now
demonstrate that Hh-activated mesenchyme functionally interacts with airway progenitors to promote
metaplastic KRT5 differentiation in the fibrotic lung. Furthermore, we show that a Hh-BMP signaling
circuit in the airway progenitor niche regulates the metaplastic outcome during fibrotic repair. Our central
hypothesis is that mesenchymal Hh activation upregulates BMP antagonists in the progenitor niche,
which drives epithelial metaplasia in both human and mouse lungs, and this Hh-BMP circuit can be
targeted to mitigate and reverse metaplasia in lung fibrosis. Leveraging novel genetic/pharmacologic
tools we have developed, our single and bulk RNAseq bioinformatics capacity, and our access to human
samples, this proposal aims to address how the mesenchymal compartment of the progenitor niche
modifies epithelial plasticity in fibrotic repair, and outlines a potential pre-clinical pipeline to identify
compounds that can target epithelial metaplasia in lung fibrosis.

## Key facts

- **NIH application ID:** 10095587
- **Project number:** 1R01HL155622-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Tien Peng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $586,537
- **Award type:** 1
- **Project period:** 2021-02-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10095587

## Citation

> US National Institutes of Health, RePORTER application 10095587, Mesenchymal modulation of epithelial metaplasia in lung fibrosis (1R01HL155622-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10095587. Licensed CC0.

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