# Project 1: Mast cell orchestration of epithelial and neuronal responses

> **NIH NIH P01** · FOOD ALLERGY SCIENCE INITIATIVE, INC. · 2024 · $586,250

## Abstract

PROJECT SUMMARY
Food allergy is associated with a hypersensitive type 2 immune response that develops following sensitization
to food proteins. Allergic sensitization elicits the development of adaptive immune memory, characterized by
antigen specific B-cells that produce antibodies of the IgE and IgG1 isotypes. IgE antibodies bind to tissue-
resident mast cells, and these IgE-mast cell units enable a rapid and exuberant responses to low quantities of
food antigen. Pre-clinical and clinical studies underscore the importance of IgE antibodies in the
gastrointestinal manifestation of food allergy, such as abdominal pain, nausea, and vomiting; however, how
this hypersensitive state is established and what mast-cells induce to initiate these symptoms are poorly
understood. The overarching hypothesis of this proposal is that close symbiotic interactions between mast cells
and epithelial cells enable intraepithelial mast cell expansion within the allergic intestines, and that mast cells in
turn alter both the transcriptional state and differentiation of intestinal epithelium to mediate their effects on
food allergy symptoms. Preliminary data in in vivo food allergy models demonstrates marked intraepithelial
mast cell expansion in food allergic mice, with the greatest frequencies found in the proximal small intestine in
the crypt/transit amplifying zone. We further identified a leukotriene transcriptional signature in the intestines of
food allergic mice, which was largely confined to the intraepithelial layer and was dependent on IgE and FceR1
expressing cells. Consistently, pharmacological and genetic disruption of cysteinyl leukotriene synthesis was
found to dramatically blunt intestinal symptoms of food allergen ingestion, with separate cysteinyl leukotriene
receptors mediating the acute behavioral (CysLTR2) and physiological effects (CysLTR1) to allergen. We
hypothesized that mast-cell epithelial cross talk through cysteinyl leukotrienes may contribute to symptoms
such as allergen induced malaise. In support of this, we find mast cells induce transcription of the stress-
related TGFb cytokine, GDF15, from colonic crypt epithelial cells via a CysLTR1 dependent mechanism, and
that GDF15 blockade ameliorates late phase avoidance behavior to allergen. This proposal aims to build upon
these findings through the following aims: Aim 1 will examine IgE-dependent transcriptional and cell
composition changes in the intestinal epithelium and will identify candidate epithelium-derived mast cell growth
factors in vitro and in vivo, Aim 2 will clarify the role of cysteinyl leukotrienes and their receptors in food allergy
pathogenesis using pharmacological inhibitors, genetic knockouts, and CysLTR1-3 floxed mice, and Aim 3 will
examine the transcriptional state of GDF15+ epithelial cells induced by food allergy and will investigate the
behavioral and immunological effect of GDF15 and GFRAL deficiency using newly generated KO mice on the
BALB/cJ background. Togeth...

## Key facts

- **NIH application ID:** 10762663
- **Project number:** 1P01AI179273-01
- **Recipient organization:** FOOD ALLERGY SCIENCE INITIATIVE, INC.
- **Principal Investigator:** Ruslan Medzhitov
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $586,250
- **Award type:** 1
- **Project period:** 2024-05-14 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10762663

## Citation

> US National Institutes of Health, RePORTER application 10762663, Project 1: Mast cell orchestration of epithelial and neuronal responses (1P01AI179273-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10762663. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*