# Pathogenesis of frequent asthma exacerbators

> **NIH NIH F30** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $41,915

## Abstract

ABSTRACT
Asthma is one of the most common non-communicable illness among children in the United States. This disease
is comprised of multiple pathobiological subgroups, also known as endotypes, which have distinct pathologies
and differential responses to treatment. Clinical evidence has identified an endotype of asthma comprised of
individuals who are frequently (≥2 times per 12 months) hospitalized for an asthma exacerbation. While there
have been previous studies examining the clinical characteristics of the frequent exacerbator (FE) endotype, the
heterogeneity of the populations studied makes findings difficult to generalize to pediatric populations.
Additionally, there have been no studies examining the underlying biological differences which may be
responsible for recurrent exacerbations. To answer these questions, we have leveraged the Ohio Pediatric
Asthma Repository (OPAR), the first statewide repository of patients admitted for an asthma exacerbation at any
of the 6 major pediatric medical centers. In addition to clinical and epidemiologic data, biosamples (nasal
epithelial cells, blood, etc) are stored in our laboratory at Cincinnati Children’s Hospital, allowing us a unique
opportunity to explore the biologic underpinnings of the FE endotype. In our first study, we performed RNA-
sequencing (RNA-seq) of upper airway epithelial cells and found: (a) FEs are a biologically distinct endotype of
pediatric asthma; (b) the transcriptome of FEs is characterized by an increase in expression of gene modules
enriched for nervous system processes; (c) non-FEs (nFEs) show an increase in gene modules enriched for
allergic immunity as has been described previously in asthma; and (d) increased expression of modules enriched
for nervous system processes in individuals with >2 annual exacerbations, regardless of whether it was the 2nd
or the 7th. We also have preliminary data showing differences in methylation patterns between FEs and nFEs
indicative of epigenetic changes coupled with our transcriptomic results. Together, our findings and existing
literature suggest a durable molecular shift in the airways which predisposes an individual for frequent asthma
exacerbations. Therefore, we hypothesize the unique transcriptional divergence exhibited in the airways
of FEs is a durable change characterized by cell-specific epigenetic and gene expression changes. We
propose to test this hypothesis by: (i) collecting samples from FEs during an exacerbation and a period of normal
lung function to assess gene expression durability (Aim 1), and (iii) generate single cell RNA-seq and ATAC-
seq datasets to determine cell-specific patterns of expression and gene regulatory networks associated with
frequent asthma exacerbations (Aim 2). Our studies will further define the molecular etiology of this important
pediatric asthma endotype and provide putative targets for therapeutic intervention.

## Key facts

- **NIH application ID:** 10995701
- **Project number:** 1F30HL172613-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Kieran Phelan
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,915
- **Award type:** 1
- **Project period:** 2024-09-07 → 2027-09-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995701

## Citation

> US National Institutes of Health, RePORTER application 10995701, Pathogenesis of frequent asthma exacerbators (1F30HL172613-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10995701. Licensed CC0.

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