# Type 2 Immunity Elicited Through an LTE4/GPR99-Dependent Pathway

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $596,121

## Abstract

Project Summary
 LTE4 is the stable cysteinyl leukotriene (cysLT), detected in the biologic fluids of patients with asthma
triggered by allergen challenge, aspirin, and respiratory viruses. LTE4 elicits cutaneous edema in normal
controls and elicits basophil and eosinophil recruitment to the lung in patients with asthma. Our group recently
identified CysLT3R (also called Oxgr1 or GPR99) as the high affinity receptor for LTE4 and demonstrated that it
mediates LTE4-elicited cutaneous edema in mice lacking the conventional cysLT receptors, CysLT1R and
CysLT2R. However, the mechanism(s) by which LTE4 induces lung pathobiology remains poorly understood
and the role of CysLT3R has not been elucidated. We have found that CysLT3R is expressed on both murine
and human respiratory epithelial cells (EpCs) and controls both their activation and development. As CysLT3R
is resistant to currently available cysLT receptor inhibitors, the findings from this proposal will determine
whether CysLT3R is a logical therapeutic target to reduce mucus production, airflow obstruction, or type 2
inflammation in asthma.
 Using single cell RNA-Seq and a novel CysLT3R floxed strain that we have developed, in addition to
several lineage reporter and null strains, Aim 1 will define the cellular mechanisms by which CysLT3R
regulates murine lung EpC activation and development. In Aim 2, we will characterize candidate effector
pathways in CysLT3R-expanded airway EpCs that we have defined in an RNA-seq dataset. This aim proposes
to expand our RNA-seq data on a purified rare EpC subset, and use a cell-specific knockout to characterize an
EpC effector protein of interest. In Aim 3 we will take advantage of a growing single cell RNA-seq data base
we are developing from patients with nasal polyps. We will exploit the tremendous transcriptional distinction we
see across different disease states (aspirin-exacerbated respiratory disease, aspirin-tolerant patients with
nasal polyposis, and control samples) to look for unique EpC effector programs and define those which may be
regulated by CysLT3R. Finally, we will use an in vitro system in normal human bronchial epithelial cell culture
to determine the extent to which CysLT3R regulates human airway EpC differentiation and validate the
pathways through which this occurs.

## Key facts

- **NIH application ID:** 9841901
- **Project number:** 5R01AI134989-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Nora Amanda Barrett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $596,121
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841901

## Citation

> US National Institutes of Health, RePORTER application 9841901, Type 2 Immunity Elicited Through an LTE4/GPR99-Dependent Pathway (5R01AI134989-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9841901. Licensed CC0.

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