# Genetic and Epigenetic Programming of Allergic Airway Inflammation

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2024 · $677,996

## Abstract

It is appreciated that the high prevalence of asthma over the last decades reflects the interaction of susceptibility
genes in affected individuals with environmental and social changes ushered by modernity [1]. A key feature of
asthma is chronic airway inflammation driven and/or exacerbated by ongoing exposure to allergens and
pollutants, most notably ambient particulate matter (PMs). The persistence of such inflammation suggests the
derailment of normative countervailing immune regulatory mechanisms that would otherwise limit its scope. In
that regard, we have identified Notch4 expression in lung regulatory T (TR) cells as a key mechanism that disrupts
lung tissue homeostatic immune regulation to promote allergic airway inflammation. Notch4 is upregulated by
IL-6 signaling in TR cells to activate downstream intermediates including the Wnt and Hippo pathways to promote
airway Th2 and Th17 immune responses, respectively. Notch4 expression is augmented by PM, which act to
induce the expression of the Notch receptor ligand Jag1 in alveolar macrophages as well as the production of
IL-6. Finally, Notch4 is also upregulated on lung TR cells in the context of viral infections, thus providing a potential
link between viral infections and exacerbation of allergic airway inflammation. Accordingly, our central hypothesis
is that Notch4 signaling in TR cells integrates cues by allergens, pollutants and viruses to license tissue allergic
inflammation. To address this hypothesis, we propose under Aim 1 to investigate the mechanisms by which
Notch4 subverts TR cell function to promote allergic airway inflammation. We will investigate the role of the
Notch4-activated Hippo pathway in TR cell destabilization, leading to the generation of tissue resident ex-TR cells
that promote airway inflammation. We will also investigate the role of the Wnt pathway downstream of Notch4 in
driving Th2 pathology, as well as the interaction of Notch4 with environmental inputs such as PMs of different
sources and physiochemical properties to promote airway inflammation. We further propose under Aim 2 to
investigate the role of Growth and Differentiation Factor 15 (GDF15) as a cytokine produced by lung TR cells in
a Notch4-Wnt pathway-dependent manner that may contribute to tissue inflammation and pathology by acting
via its receptor GFRAL on ILC2 to drive their activation and expansion. The relationship between TR cell Notch4,
GDF15, IL-6 and BMI will be explored in a cohort of asthmatic subjects. Finally, under Aim 3 we will examine
the role of TR cell-intrinsic viral sensing pathways alone and in synergy with Notch4 in promoting virus and
allergen-induced inflammation. Our studies will help elucidate novel mechanisms fundamental to the biology of
allergic airway inflammation and its augmentation by pollutants, obesity and viral infections.

## Key facts

- **NIH application ID:** 10783089
- **Project number:** 5R01AI065617-23
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Talal Amine Chatila
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $677,996
- **Award type:** 5
- **Project period:** 1998-08-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10783089

## Citation

> US National Institutes of Health, RePORTER application 10783089, Genetic and Epigenetic Programming of Allergic Airway Inflammation (5R01AI065617-23). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10783089. Licensed CC0.

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