# Identification of a Wnt/ Beta-catenin responsive adult lung epithelial progenitor cell for tissue repair in chronic lung disease

> **NIH NIH F32** · UNIVERSITY OF COLORADO DENVER · 2020 · $69,306

## Abstract

Project Summary/Abstract
The goal of this proposal is to determine the potential of endogenous epithelial progenitor cells to contribute to
regenerative approaches for emphysema therapies. Emphysema is a major phenotype of chronic obstructive
lung disease (COPD) and affects over 4 million people in the US. It is characterized by progressive loss of
alveolar lung tissue without therapies that stop or reverse the disease. Importantly, the endogenous ability of the
distal lung to activate self-repair mechanisms is defective in emphysema, raising the question why and which
regenerative pathways and/or cells are silenced in emphysema. WNT/beta-catenin signaling has been recently
identified as a potential regenerative pathway with reduced activity in emphysema and re-activation of WNT/beta-
catenin signaling has been shown to initiate intrinsic lung tissue repair. However, the mechanisms and the
identity of potential progenitor cells that respond to WNT/β-catenin signaling and contribute to the repair of tissue
destruction in chronic lung diseases, remain unknown. My preliminary studies using transgenic Wnt/beta-catenin
activity reporter mice and a progenitor cell derived 3D lung organoid assay have identified a unique lung epithelial
population which forms airway and alveolar organoids and exhibits high sensitivity to the modulations of
WNT/beta-catenin signaling, thus representing a WNT/beta-catenin responsive progenitor population. Further,
population and single cell transcriptome analysis has led to the identification of an airway club cell progenitor
population as the major cell type in the WNT/beta-catenin responsive population. Thus, the aim of this proposal
is to address the central hypothesis that WNT/beta-catenin signaling activates club cells to regenerate alveolar
tissue in the emphysematous lung. This hypothesis will be tested in 3 Specific Aims: 1). Test the hypothesis that
the club cell population is WNT/beta-catenin responsive and forms organoids; 2). Determine the fate and
phenotype of the club cell population in murine emphysema models in vivo and their regenerative capacity upon
WNT/beta-catenin activation; 3). Test the hypothesis that the club cell population respond to WNT/beta-catenin
activation in human emphysematous lung tissue.
The proposed work will solve an existing challenge by defining a precise WNT/beta-catenin-responsive club cell
population in both mouse and human lungs and by identifying novel marker genes allowing to elucidate their
alterations and regenerative potential in emphysema. This work and the integrated training plan will allow the
investigator to establish comprehensive knowledge on lung injury and regeneration and expertise and skills to
subsequently define the molecular mechanism leading to successful lung tissue regeneration in a future
independent research career.

## Key facts

- **NIH application ID:** 10001340
- **Project number:** 5F32HL149290-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Yan Hu
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,306
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001340

## Citation

> US National Institutes of Health, RePORTER application 10001340, Identification of a Wnt/ Beta-catenin responsive adult lung epithelial progenitor cell for tissue repair in chronic lung disease (5F32HL149290-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10001340. Licensed CC0.

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