# Project 2: Micro-RNA and ER stress regulation of pathological mucus in type 2-high asthma

> **NIH NIH U19** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $484,500

## Abstract

PROJECT 2 SUMMARY
Mucus plugging is common in severe asthma, is associated with type 2 inflammation and poor lung function and
persists despite high dose inhaled corticosteroids. Mucus plugging is also a critical feature of fatal asthma.
Consequently, although we have made significant progress in targeting airway inflammation in asthma, there is
still an unmet need for therapeutic approaches that directly prevent or treat pathological mucus and mucus
plugging. The overall objectives of this project are to understand the molecular mechanisms that regulate the
differentiation and function of goblet cells that produce airway mucins and secrete pathological mucus in human
asthma and to develop pre-clinical data on two novel therapeutic approaches that target these processes. In Aim
1, we propose to determine the roles of miR-141/200 family members in epithelial cell differentiation, pathological
mucus production, and airway mucus plugging in asthma. Of the highly homologous five-member miR-141/200
miRNA family, our preliminary data implicate miR-141 in goblet cell differentiation, mucin production and mucus
secretion. However, our data suggest that other members of this microRNA family also play a role in these
processes. We propose to test the hypothesis that miR-141/200 family members are important for the transition
of basal cells to secretory cells, mucin production and mucus secretion, playing roles that are complementary
(or even antagonistic) to miR-141. We will also test the hypothesis that these miR-141/200 family members
localize to epithelial cells at sites of type 2 inflammation and mucus plugging in human asthma and are
associated with severe disease. In Aim 2 we propose to determine the mechanisms underlying IRE1α regulation
of secretory epithelial cell differentiation and pathological mucus production. Our preliminary data show that
endoplasmic reticulum (ER) stress, unfolded protein response (UPR) pathway activation and activation of IRE1α
kinase endoribonuclease (RNase) are increased during secretory cell differentiation in patients with asthma. We
also show that conditional deletion of IRE1α in the murine airway epithelium or inhibition with a novel small
molecule inhibitor (KIRA8) in human airway epithelial cells, inhibit goblet cell metaplasia and airway epithelial
mucin production. IRE1α may mediate these effects through two distinct outputs: an “adaptive” mode which
typically promotes homeostasis, and a “terminal” mode, which leads to maladaptive cellular outcomes. Recently
we have developed another novel small molecule inhibitor, PAIR2, which specifically inhibits the terminal mode
of UPR activation. In this aim, we propose to test the hypotheses that IRE1α inhibition decreases goblet cell
metaplasia by inhibiting the transition of basal cells into a transitional secretory cell state, that terminal UPR
activation mechanistically connects IRE1α to goblet cell metaplasia (which can be inhibited by PAIR2), and that
terminal UPR si...

## Key facts

- **NIH application ID:** 10809788
- **Project number:** 5U19AI077439-17
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** PRESCOTT G WOODRUFF
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $484,500
- **Award type:** 5
- **Project period:** 2008-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10809788

## Citation

> US National Institutes of Health, RePORTER application 10809788, Project 2: Micro-RNA and ER stress regulation of pathological mucus in type 2-high asthma (5U19AI077439-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10809788. Licensed CC0.

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