# Mucin sialylation drives epithelial cell senescence and severe asthma

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $695,967

## Abstract

This application explores the paradigm shifting hypothesis that post-translational modification (sialylation) of a
cell surface (tethered) mucin, MUC4, drives terminal differentiation and senescence of airway epithelial cells
(AECs) through inhibition of epidermal growth factor receptor (EGFR) family pathways, worsening epithelial
wound repair and asthma severity. Our proposed studies will be the first to specifically test tethered mucins and
their post-translational N-glycosylation/sialylation for a role in AEC terminal differentiation and senescence. Our
published data (Zhou et al) demonstrate that sialylation of the tethered mucin, MUC4β, i.e., MUC4α βSA, controls
goblet cell terminal differentiation as a function of β-galactoside α2,6-sialyltransferase-1 (ST6GAL1) activity.
Both ST6GAL1 and MUC4β critically lower AEC proliferative capacity, with additional published data (Inoue et
al) linking diminished AEC proliferation to abnormal wound repair in vitro. Reduced AEC proliferative capacity
may reflect reduced activation of the EGFR family member, ErbB2, a known receptor for MUC4β. New data
confirm that elevations in MUC4 and ST6GAL1 are present in severe exacerbation-prone asthma and in house
dust mite challenged mice. Elevations in both biologically associate with low intracellular glutathione (GSH) to
oxidized glutathione (GSSG) ratios (oxidative stress) and lower mitochondrial and senescence gene expression.
Parallel in vitro AEC data show T2 inflammation/IL-13 alters intracellular metabolism and mitochondria,
decreases GSH/GSSG, and further decreases wound repair. Yet, the overall impact of MUC4β and/or its
sialylation to epithelial cell phenotypes, cell senescence, and the mechanisms by which these changes contribute
to severe asthma are unclear. The studies proposed here will comprehensively evaluate the intersection of
mucins, mucin sialylation, and senescence pathway(s), while robustly testing their functional importance using
primary human AEC cell cultures and transgenic mouse models. The three proposed aims will: 1) elucidate the
mechanistic and functional impact of MUC4β and MUC4βSA on AEC terminal differentiation, senescence and
wound repair in vitro, 2) test the functional impact of Muc4βSA-AEC interactions on mucin secretion, goblet cell
hyperplasia/terminal differentiation, senescence, and wound repair in an asthma mouse model and 3) define the
relationship of MUC4βSA to senescence and AEC phenotypes in human asthma patients. These concurrent aims
will iteratively develop data that link mucins, their sialylation and fundamental senescence-related epithelial
processes to identify highly novel targets for treatment of severe asthma.

## Key facts

- **NIH application ID:** 10434719
- **Project number:** 5R01HL153058-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Richard Charles Boucher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $695,967
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434719

## Citation

> US National Institutes of Health, RePORTER application 10434719, Mucin sialylation drives epithelial cell senescence and severe asthma (5R01HL153058-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10434719. Licensed CC0.

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