# Pre-Clinical Evaluation of IRE1beta as a Novel Therapeutic Target for Cystic Fibrosis Airway Mucus Production

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $464,553

## Abstract

Cystic fibrosis (CF) lungs exhibit mucoinflammatory responses soon after birth, likely triggered by viral
infections and/or aspiration. Respiratory syncytial virus (RSV) causes bronchiolitis leading to airway muco-
obstruction in young CF children, who exhibit increases in MUC5B and MUC5AC mucins in their airways.
Because no treatments are available for CF airway mucus overproduction, there is a clear unmet medical need
for therapies that target mucin synthesis in CF airways. CF airway epithelial inflammation triggers endoplasmic
reticulum (ER) stress and activates the inositol requiring enzyme 1 (IRE1), which exists in two isoforms, α and
β. IRE1α is ubiquitous, but IRE1β is only expressed in mucous cells of the respiratory and GI tracts. We have
shown that IRE1β (but not IRE1α) is required for airway mucin production. IRE1 is an ER transmembrane protein
with a lumenal domain (sensor of unfolded proteins) and a cytoplasmic domain (effector) with kinase and RNase
activities. It is unknown whether the IRE1 lumenal domain senses unfolded mucins and whether its cytoplasmic
domains mediate mucin production; however, our previous studies suggested that mucin production triggers ER
stress and activates IRE1β kinase-induced RNase activation. Because the activated IRE1 RNase splices the
mRNA of X-box binding protein-1 (XBP-1s), a transcription factor that up-regulates mucin production, this may
provide a mechanism for CF airway epithelial mucin overproduction. In non-mucous cells, IRE1 kinase activates
JNK, p38 MAP kinase and NF-B via protein interactions, but it is unknown whether the IRE1 kinase activates
these pathways, which are relevant to CF airways because they can promote mucin production. Our preliminary
data indicate that IRE1β, MUC5AC and MUC5B levels are up-regulated in native CF human airways and in
freshly isolated CF human distal airway epithelia. Over-expression of wild type IRE1 in primary human bronchial
epithelia (HBE) increased mucin production, whereas over-expression of IRE1 mutants that lack kinase and/or
RNase activities decreased mucin production. IL-1 and TNF, predominant CF airway cytokines, differently
affected XBP-1s (only IL-1 increased XBP-1s) and mucin production (IL-1 > TNF) in HBE, suggesting that
they up-regulate mucin production via IRE1β RNase-dependent and independent mechanisms. KIRA6, an IRE1
kinase + RNase inhibitor, blunted IL-1-increased XBP-1s and mucins in CF HBE. Notably, a combination of
CFTR modulators (VX-445, VX-661 and VX-770) had no effect on mucin production. RSV infection of HBE
increased XBP-1s and mucin production/secretion, and these responses were blunted by KIRA6. Finally, murine
parainfluenza virus type 1-infected mice developed viral bronchiolitis and airway muco-obstruction, modeling the
bronchiolitis in CF infants infected by RSV. Our aims will test the role of IRE1β protein domains in CF airway
cytokine-increased mucin production in CF HBE. We will also evaluate the therapeutic ...

## Key facts

- **NIH application ID:** 10296058
- **Project number:** 1R01HL155261-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Carla Maria Pedrosa Ribeiro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $464,553
- **Award type:** 1
- **Project period:** 2021-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296058

## Citation

> US National Institutes of Health, RePORTER application 10296058, Pre-Clinical Evaluation of IRE1beta as a Novel Therapeutic Target for Cystic Fibrosis Airway Mucus Production (1R01HL155261-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10296058. Licensed CC0.

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