# Targeting early events in MUC5B-driven lung injury and fibrosis

> **NIH NIH P01** · UNIVERSITY OF COLORADO DENVER · 2024 · $598,827

## Abstract

PROJECT SUMMARY
The overall goal of Project 3 is to understand how increased misexpression of MUC5B in distal airways leads to
honeycomb cyst formation, fibroblast accumulation, pro-fibrotic programming and ultimately fibrosis in response
to distal airway and alveolar epithelial injury. Through a combination of in vivo studies in mouse models and in
vitro studies with human lung epithelial cells and fibroblasts, Project 3 seeks to fill this knowledge gap by testing
the hypothesis that MUC5B misexpression and persistent ER stress in distal airway epithelial cells creates
susceptibility to apoptosis in both alveolar epithelial cells and distal airway epithelial cells leading to
fibrosis and honeycomb cyst formation, respectively. We will address mechanistic questions about: (i) how
MUC5B misexpression by distal airway epithelial cells creates vulnerability to apoptosis induction leading to
fibroblast accumulation, pro-fibrotic programming, fibrosis and honeycomb cyst formation, (ii) the relative role(s)
of alveolar and distal airway epithelial cell apoptosis in the development of fibrosis and honeycomb cysts, and
(iii) from a remedial perspective, if prevention of epithelial cell apoptosis mitigates the development of pulmonary
fibrosis and honeycomb cyst formation. While much has been learned about the role of alveolar epithelial cell
apoptosis in the development of fibrosis, most of these studies were conducted prior to the discovery of increased
IPF susceptibility conferred by MUC5B misexpression. Project 3 seeks to address this knowledge gap. Aim 1
will test the hypothesis that alveolar epithelial cell apoptosis, in the context of increased distal airway Muc5b
misexpression, leads to fibrosis, but not honeycomb cyst formation in mice. This hypothesis will be tested using
an alveolar epithelial cell ablation strategy in the context of Muc5b misexpression in distal airway epithelial cells
to define the importance of alveolar epithelial cell apoptosis in the development of fibrosis. Aim 2 will test the
hypothesis that induction of distal airway epithelial cell apoptosis in the context of increased distal airway Muc5b
misexpression promotes honeycomb cyst formation in mice. This hypothesis with be tested using a distal airway
epithelial cell ablation strategy. Aim 2 will also provide insight into the question of whether distal airway epithelial
cell apoptosis and honeycomb cyst formation in the context of Muc5b misexpression indirectly leads to alveolar
replacement and fibrosis. Lastly, Aim 3 will test the hypothesis that prevention of alveolar and distal airway
epithelial cell apoptosis even in the context of increased distal airway Muc5b misexpression will prevent
persistent fibrosis and honeycomb cyst formation. While increased MUC5B expression in distal airways is a risk
factor for the development of fibrosis and honeycomb cysts in IPF patients, little is known about the fundamental
mechanisms that connect these events. Though extensive integra...

## Key facts

- **NIH application ID:** 10815877
- **Project number:** 5P01HL162607-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** David W. Riches
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $598,827
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815877

## Citation

> US National Institutes of Health, RePORTER application 10815877, Targeting early events in MUC5B-driven lung injury and fibrosis (5P01HL162607-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10815877. Licensed CC0.

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