# Determining drivers of mast cell expansion and function during human airway disease

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $715,968

## Abstract

Project Summary/Abstract:
Mast cells (MCs) expand within the airway epithelium and sub-epithelium during prevalent and burdensome
human respiratory disease, including asthma and nasal polyposis, where they are thought to play a central role
in disease pathobiology. MCs take on discrete protease expression profiles in each location, with sup-epithelial
MCs co-expressing tryptase and chymase (MCTC) while epithelial MCs express tryptase alone (MCT). Neither
the mechanisms underlying this expansion, the signals directing the epithelial and sub-epithelial MC
phenotypes, nor the differential contribution of MC phenotypes to tissue inflammation are well understood. This
application focuses on understanding the mechanisms through which airway tissue structural cells differentially
direct the expansion and differentiation of MC progenitors (MCps), based on preliminary studies identifying a
central role for fibroblasts and epithelial cells in both processes. This proposal tests the central hypothesis that
MC hyperplasia in inflamed human airway mucosa is driven by the recruitment of MCps exhibiting a robust
proliferative capacity, and that the proliferation and differentiation of these recruited MCps towards the
histochemically recognized MCT and MCTC subsets are driven by key signals secreted by airway structural
cells. A related hypothesis is that the resulting intraepithelial and subepithelial MC phenotypes are maintained
through a network of transcription factors regulated by these tissue stromal-derived signals, and that signal
nucleotide polymorphisms in these transcription factors increase risk of developing airway disease. Aim 1 of
this proposal evaluates MCp concentration in human sinonasal tissue across disease endotypes, determining
the relationship between recruited MCp and the proliferative population of MCs we previously identified in
nasal polyposis. Aim 2 of this proposal tests the impact of a series of candidate stromal-derived ligands on
directing MCp proliferation and differentiation using CRISPR/Cas9 gene editing. Aim 3 probes the transcription
factor network underlying MC polarization via shRNA knockdown and evaluates the impact of key asthma-
associated single nucleotide polymorphisms in one such transcription factor on intraepithelial MC
differentiation. Completion of these aims will greatly expand our understanding of the pathways through which
MCs are capable of influencing tissue inflammation and the mechanism(s) through which these pathways are
regulated by their tissue microenvironment.

## Key facts

- **NIH application ID:** 10940784
- **Project number:** 1R01HL174622-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Daniel F Dwyer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $715,968
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940784

## Citation

> US National Institutes of Health, RePORTER application 10940784, Determining drivers of mast cell expansion and function during human airway disease (1R01HL174622-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10940784. Licensed CC0.

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