# Project 4: Notch regulation of COPD-associated goblet cell hyperplasia/metaplasia

> **NIH NIH P20** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2021 · $321,775

## Abstract

Abstract. Chronic obstructive pulmonary disease (COPD) is the major smoking-induced lung disorder for
which there is no cure. Changes in the airway epithelium architecture in response to cigarette smoking play a
critical role in COPD pathogenesis. Goblet cell hyperplasia or metaplasia is an epithelial remodeling phenotype
characterized by increased numbers of mucus-producing (“goblet”) secretory cells. In association with decreased
ciliated cell numbers, these changes culminate in excess mucus production and impaired mucociliary clearance
that contribute significantly to COPD morbidity and mortality. Therefore, identifying the mechanisms by which
cigarette smoke dysregulates secretory cell differentiation in the airway epithelium is critical to
developing novel therapeutics to treat COPD. Basal cells (BC) function as stem/progenitor cells in the human
airway epithelium. Notch signaling plays a key role in regulating BC stem/progenitor function in both humans
and mice. This includes regulating the balance of BC differentiation into either secretory or ciliated cells. In vivo
human studies have identified alterations in Notch signaling components at the mRNA, protein and epigenetic
levels in the small airway epithelium (SAE) of smokers with and without COPD relative to nonsmokers. These
include increased levels of activated NOTCH1 receptor and altered expression of NOTCH3 and multiple Notch
downstream effector genes (e.g., HES5, HEY1 and HEY2). We demonstrated in vitro that constitutive activation
via the NOTCH1 and 3 receptors in nonsmoker-BC increases expression of the downstream effectors HES5,
HEY1, HEY2 and HEYL. Furthermore, NOTCH1 and 3 signaling activation increased secretory cell differentiation
with a corresponding decrease in ciliated cell differentiation characteristic of goblet cell hyperplasia/metaplasia.
Therefore, we hypothesize that cigarette smoking increases Notch signaling activity in BC
stem/progenitors resulting in development of goblet cell hyperplasia/metaplasia in the airways of
smokers with COPD. Despite Notch regulating BC differentiation and providing a potential therapeutic target to
treat COPD-associated goblet cell hyperplasia/metaplasia, important questions remain. First, what is the effect
of cigarette smoking on Notch activity in the airway epithelium (Aim 1)? Second, as BC from COPD patients
have altered regenerative capacity compared to BC from nonsmokers, does modulation of Notch activity in
COPD-BC have the same outcome as in nonsmoker-BC (Aim 2)? Third, what are the downstream effectors that
regulate Notch-mediated goblet cell differentiation (Aim 3)? To address these questions we propose the
following Aims: Aim 1. Determine whether cigarette smoke exposure activates Notch signaling in the airway
epithelium in vitro and in vivo. Aim 2. Determine whether BC stem/progenitor cells from nonsmokers vs. patients
with COPD respond differentially to Notch signaling modulation as they differentiate into a mucociliated
...

## Key facts

- **NIH application ID:** 10225577
- **Project number:** 5P20GM103636-09
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Matthew Stuart Walters
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $321,775
- **Award type:** 5
- **Project period:** 2013-03-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225577

## Citation

> US National Institutes of Health, RePORTER application 10225577, Project 4: Notch regulation of COPD-associated goblet cell hyperplasia/metaplasia (5P20GM103636-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10225577. Licensed CC0.

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