# Eosinophil functions in allergic gastrointestinal diseases

> **NIH NIH R56** · UNIVERSITY OF COLORADO DENVER · 2024 · $195,000

## Abstract

Project Summary
Eosinophilic gastrointestinal disorders (EGIDs) are a group of allergic inflammatory disorders characterized by
excessive accumulation and persistence of eosinophils and a Th2-dominant immune response. EGID
symptoms and treatments carry heavy social and psychological tolls, particularly in affected children. Despite a
worldwide increase in prevalence, the natural disease course of EGIDs is unknown, and treatment options
limited to food allergen avoidance and oral corticosteroids. Eosinophils are innate immune leukocytes that
constitutively home to the small and large intestine in the steady state where they contribute to immune, tissue,
and microbiome homeostasis. Why and how eosinophils shift to pathologic roles, and what those pathologic
roles are within the context of EGIDs, is unknown and represents a fundamental knowledge gap hindering the
development of needed therapeutic approaches. Our published studies during the previous funding cycle
contributed to an evolving paradigm in eosinophil biology that now recognizes the existence of tissue-specific
adaptations and distinct functional phenotypes within mucosal organs. We demonstrated morphologic, spatial
and phenotypic heterogeneity of intestinal eosinophils, proposed a framework to stratify tissue eosinophils with
“homeostatic” versus “inflammatory” potentials, and traced sub-phenotype versatility in situ within the contexts
of local allergic, and systemic non-specific, inflammation. These studies provide a scaffolding for functional
outcomes and spatial mapping proposed in this renewal application. Our preliminary data also show that notch
2 signaling is active in human blood eosinophils, drives a cytokine-activated transcriptome, and is required for
cytokine-mediated survival. To explore notch 2 signaling in vivo we generated a new mouse line with
eosinophil-targeted deletion (EoN2). EoN2 mice exhibit impaired intestinal tissue-specific adaptations of
eosinophils at baseline, and the selective loss of a villus-migrated, putatively “inflammatory” eosinophil subset
in an allergen-driven EGID model. Building on and extending these findings, this renewal application applies
novel tools created in the first cycle to explore the overarching hypothesis that notch 2 signaling underlies
intestinal tissue specific adaptations of eosinophils in the steady state and regulates their functional
phenotypes in inflammation. Aim 1 uses complementary high dimensional flow cytometry and multispectral
imaging to define and integrate eosinophil functional subsets with spatial mapping and translate advances in
profiling and spatial mapping to active EGID patient biopsies. Aim 2 exploits notch 2-dependent regulation of
eosinophils to investigate functional phenotypes within the context of allergic inflammation. Aim 3 uses genetic
and pharmacologic approaches to trial therapeutic targeting of notch 2 in mouse models of EGIDs. Completion
of these aims will provide fundamental insights into the regu...

## Key facts

- **NIH application ID:** 11059637
- **Project number:** 2R56AI121186-07A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Lisa Ann Spencer
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $195,000
- **Award type:** 2
- **Project period:** 2024-05-10 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11059637

## Citation

> US National Institutes of Health, RePORTER application 11059637, Eosinophil functions in allergic gastrointestinal diseases (2R56AI121186-07A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11059637. Licensed CC0.

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