# Type 2 Inflammation and Remodeling Elicited Through an LTE4/OXGR1-dependent pathway

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $760,583

## Abstract

PROJECT SUMMARY
Tuft cells are a specialized epithelial cells (EpCs) that initiate airway type 2 inflammation (T2I) through their
generation of IL-25 and pro-inflammatory lipid mediators, cysteinyl leukotrienes (CysLTs). We previously
reported that airway tuft cells are indirectly activated by common aeroallergens through damage-associated
molecular patterns (DAMPs), including the release of ATP and the activation of P2Y2 on tuft cells. Because tuft
cells recognize tissue damage, and are detected in settings of airway injury in mouse and humans, we and
others have speculated that they may have a role in lung repair, but thus far no such function has been
demonstrated and the mechanism(s) by which tuft cells develop in the distal airways are unknown.
 Our preliminary data demonstrate an important feed forward loop by which tuft cells promote airway
remodeling. We find that, in the setting of established inflammation, murine tracheal tuft cells generate CysLTs,
activate several airway epithelial progenitor populations that express the leukotriene E4 receptor OXGR1, and
drive aberrant airway remodeling. Importantly, we find that elements of the tuft cell and regenerative pathways
seen in the murine trachea, are also expressed in allergen-challenged murine lung, and in the sinonasal
mucosa of patients with the chronic rhinosinusitis with nasal polyposis (CRSwNP). This grant aims to define
tuft cell and CysLT influence on wound repair in these settings, and to define the functional sequelae. To
examine this, Aim 1 and 2 will use two murine models of tracheal and lung T2I. Several fate-labelled reporter
mice will be tracked and crossed to null strains. Bulk and scRNA-seq will be used to define the altered
molecular pathways in regenerating epithelium and several functional assays will be tested. Aim 3 will assess
airway repair in patients with CRSwNP using scRNA-seq, spatial multiplexed fluorescent in situ hybridization,
and ex vivo analysis. The resulting information will allow us to understand immune epithelial cross talk in the
human airway and the role of CysLTs and OXGR1 in driving remodeling.

## Key facts

- **NIH application ID:** 10744309
- **Project number:** 2R01AI134989-06
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Nora Amanda Barrett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $760,583
- **Award type:** 2
- **Project period:** 2018-02-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10744309

## Citation

> US National Institutes of Health, RePORTER application 10744309, Type 2 Inflammation and Remodeling Elicited Through an LTE4/OXGR1-dependent pathway (2R01AI134989-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10744309. Licensed CC0.

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