# Epithelial cell reprogramming and mucus gel pathology in self-sustaining type 2 airway niches in asthma

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $562,594

## Abstract

Project Summary / Abstract
Type 2 inflammation is initiated at the airway epithelium through the release of master cytokines such as IL-33
that drive type 2 cytokine production, eosinophilia, and mucus pathology. Tyope 2 inflammation becomes
persistent when homeostatic mechanisms that normally contain it fail causing persistent disease. We find that
lung imaging (computed tomography) frequently reveals mucus plugging in asthmatic airways and that the plugs
are highly eosinophilic and persist for many years. These findings lead us to propose that airway injury leads to
reprogramming of the epithelium to cause focal areas of type 2 inflammation and mucus plugging (“type 2 airway
niches”). We have three Aims to characterize the biology of type 2 niches in asthma with an emphasis on
reprogramming of immune cells and epithelial cells and on IL-13 driven mechanisms of mucus plug formation.
AIM 1 will characterize the subtypes of immune cell, their receptor expression, and their niche specific gene
expression. We will use mass cytometry (CyTOF) to enumerate type 2 cytokine producing cells and their receptor
expression repertoire. AIM 2 will character epithelial cells in the niche using bulk and single cells sequencing
and also methods to uncover niche-specific epigenetic changes in these cells with a focus on genes that regulate
type 2 cytokines (IL-33, TSLP, IL25, IL1β). ATAC-seq and whole genome methylation studies will be included
to characterize epigenetic changes in epithelial cells from plugged and non-plugged airways. AIM 3 will explore
how cross-talk between epithelial cells and eosinophils results in mucus plug formation in the type 2 airway
niche. Emphasis in this aim will be placed on IL-13 regulated pathways that caused epithelial cells to upregulate
transport of redox-relevant halides such as thiocyanate and to increase section of mucin-like molecules such as
FcγBP. To achieve its three aims, Project 3 will interact closely with projects 1 and 2, and it will take advantage
of all cores, especially the resources of the human subjects core and the analytic capabilities of Core C. Our
project will advance knowledge of the type 2 niche in ways that could point to novel treatment strategies to switch
off type 2 inflammation and fundamentally modify asthma.

## Key facts

- **NIH application ID:** 10226878
- **Project number:** 5P01HL107202-08
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** John V Fahy
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $562,594
- **Award type:** 5
- **Project period:** 2012-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226878

## Citation

> US National Institutes of Health, RePORTER application 10226878, Epithelial cell reprogramming and mucus gel pathology in self-sustaining type 2 airway niches in asthma (5P01HL107202-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10226878. Licensed CC0.

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