# The unfolded protein response and TGF-Beta signaling in pulmonary fibrosis

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $71,430

## Abstract

Project Summary/Abstract
 Idiopathic pulmonary fibrosis (IPF) is a disease of progressive interstitial fibrosis, which leads to severe
debilitation and eventually respiratory failure and death. Recent studies have implicated endoplasmic reticulum
stress (ER stress) and the resulting unfolded protein response (UPR) in the pathophysiology of pulmonary
fibrosis, including findings of increased UPR signaling and epithelial cell apoptosis in patients with hereditary
and sporadic IPF. Despite these observations, it remains unclear how UPR activation leads mechanistically to
fibrosis. The laboratory of Dr. Feroz Papa (co-sponsor) has developed KIRA8, a highly specific small molecule
inhibitor of IRE1α, the most deeply-conserved mediator of the UPR. In unpublished work, the Sheppard and
Papa laboratories (sponsor and co-sponsor, respectively) have shown that KIRA8 decreases markers of
fibrosis in mice exposed to bleomycin. TGFβ is a well-established driver of tissue fibrosis. Mice lacking integrin
αvβ6, a critical activator of extracellular, latent TGFβ, exhibit decreased UPR signaling and are
correspondingly protected from fibrosis. In the MLE12 lung epithelial cell line, KIRA8 inhibition of IRE1α
decreases SMAD2 phosphorylation, an early step in the TGFβ signaling pathway. Together, these data
suggest the central model of the proposal: that TGFβ and UPR signaling conspire to promote excessive
collagen deposition and pathological fibrosis. The proposed research will dissect the molecular mechanisms by
which the UPR enhances TGFβ signaling and fibrosis. The first aim of the study seeks to identify and
characterize the relevant cell types undergoing ER stress in the lungs of mice exposed to bleomycin, using
immunofluorescence staining and cell-type specific purification of messenger RNA (mRNA) and microRNA
(miRNA) from epithelial cells and fibroblasts. The second aim of the study will probe interactions between
TGFβ signaling and the UPR in cell lines and mice. Because IRE1α is known to modulate miRNAs that are
thought to regulate components of the TGFβ signaling pathway, modulation of miRNAs is likely to be a
mechanism by which the UPR enhances TGFβ signaling. In cell lines, TGFβ signaling will be evaluated after
the UPR has been activated or inactivated by chemical and genetic techniques. Levels of miRNAs, particularly
miR-17, miR-200, and miR-150, will be measured by quantitative PCR, and regulation of candidate miRNA
targets evaluated by dual luciferase assay. These results will be extended in vivo by analyzing mRNA and
miRNA purified from epithelial cells and fibroblasts. The proposed studies will advance the fundamental
understanding of the mechanisms of pulmonary fibrosis and offer novel targets for therapy of this devastating
disease.

## Key facts

- **NIH application ID:** 9907860
- **Project number:** 5F32HL145990-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Vincent Churk-man Auyeung
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $71,430
- **Award type:** 5
- **Project period:** 2019-03-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9907860

## Citation

> US National Institutes of Health, RePORTER application 9907860, The unfolded protein response and TGF-Beta signaling in pulmonary fibrosis (5F32HL145990-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9907860. Licensed CC0.

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