# Role of the ER stress transcription factor XBP1S in the development of idiopathic pulmonary fibrosis

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $417,233

## Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and end-stage lung disease of unknown etiology and
no cure. It is likely that genetic changes increase a person's risk of developing IPF, and then exposure to certain
environmental factors and/or aging trigger the onset of the disease. The MUC5B promoter variant rs35705950
is present in ∼50% of individuals with IPF and is recognized as the strongest known risk factor (genetic and
otherwise) for the development of IPF. This variant leads to overexpression of MUC5B mRNA and protein in
both distal airway epithelia and honeycomb cysts in the peripheral lung. These observations raise the question
of why excessive MUC5B expression in distal airways is associated with IPF? Recently, our laboratory identified
for the first time that the ER stress transcription factor XBP1S is highly expressed in the epithelium lining the
distal airways and honeycomb cysts of IPF lung, activates MUC5B gene expression by direct binding to its
promoter. Further, XBP1S differentially regulating the MUC5B promoter variant. These data connected activation
of ER stress with excessive MUC5B expression in a promoter variant-dependent model likely impairs mucociliary
clearance and function of distal airway stem cells that increase susceptibility of development of pulmonary
fibrosis. We hypothesize that activation of XBP1S induces MUC5B expression in the distal airways that
promotes pulmonary fibrosis. To test this central hypothesis, we propose the following aims: 1) XBP1S-
mediated MUC5B secretion in distal airway epithelium enhances susceptibility to development of
pulmonary fibrosis in vivo. We will assess the role of XBP1S by exposing Xbp1 airway epithelium-specific
overexpression or deletion mice to bleomycin induced respiratory epithelial injury. 2) XBP1S-mediated MUC5B
secretion impairs distal airway stem cell function to repair peripheral lung epithelia after injury. We will
utilize mouse airway epithelium-lineage tracing system and in vitro 2-D and 3-D differentiation assays to evaluate
the role of XBP1S and mucin in maintenance of the airway stem cell homeostasis in response to injury. 3)
Activation of XBP1S and presence of MUC5B promoter variant cause abnormal mucus secretion,
impaired mucociliary clearance and activation of myofibroblast differentiation. We will analyze the
biochemical and biophysical properties of the secreted mucus and electrophysiology of the DAE carrying the
MUC5B promoter variant rs35705950 at baseline and after activation of ER stress. We will also test whether
XBP1S-expressing DAE carrying the MUC5B promoter variant and/or hypoxia-induced epithelial injury directly
promotes myofibroblast differentiation. Completing the aims proposed in this application will provide novel
mechanisms underlying ER stress-mediated excessive mucin secretion by DAE promotes pulmonary fibrosis.
These mechanistic studies will likely identify novel biomarkers for early diagnosis as well as therapeutic targets
(e.g., s...

## Key facts

- **NIH application ID:** 10099794
- **Project number:** 1R01HL155951-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Gang Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $417,233
- **Award type:** 1
- **Project period:** 2020-12-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10099794

## Citation

> US National Institutes of Health, RePORTER application 10099794, Role of the ER stress transcription factor XBP1S in the development of idiopathic pulmonary fibrosis (1R01HL155951-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10099794. Licensed CC0.

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