# Defining Molecular Phenotypes of Exacerbation Prone Asthmatics

> **NIH NIH P01** · NATIONAL JEWISH HEALTH · 2020 · $1,786,716

## Abstract

Viral exacerbations of asthma are responsible for 1.8 million emergency room visits and 0.4 million
hospitalizations in the US each year, constituting a major public health problem and economic burden. Human
rhinoviruses (HRVs) are the dominant instigators of asthma exacerbations in children and adults, but the
mechanisms by which these viruses cause exacerbations are poorly understood. This application seeks to
use new approaches to identify pediatric patients who are likely to progress to exacerbation with HRV infection,
and develop new agents to prevent exacerbations. In these studies we will compare 100 exacerbation-prone
asthmatic children with several control cohorts and follow them longitudinally. For each subject we will sample
their “environmental exposure cloud” using personal exposure monitors (Project 1). We will determine how
the exposure cloud influences exacerbations and identify the constituents that produce exacerbations with the
highest frequency. Subjects will have their nasal epithelium sampled for determining their transcriptomic
profiles (Project 2). Nasal epithelial cells will also be grown in air-liquid interface cultures and the transcriptome
will be analyzed after IL-13, tobacco smoke and HRV challenge. In parallel, we will examine the epigenetic
landscape of the CD4+ T cells from each subject and determine how molecular programming regulates the
immune activity contributing to exacerbation-prone asthma (Project 3). We will also probe for crosstalk
between epithelial cells and CD4+ T cells by testing if the epithelial cells produce factors that alter the
epigenetics of the lymphocytes. The analyses of epithelial cells and CD4+T cells will be examined in the
context of environmental exposures and clinical outcomes. In project 4 we will examine the activity of
pulmonary surfactant protein A (SP-A) and the surfactant lipids, palmitoyl-oleoyl-phosphatidylglycerol (POPG)
and phosphatidylinositol (PI) as inhibitors of HRV infections using patient epithelial cells in culture. The
effects of surfactant components and HRV upon the epithelial transcriptome will be investigated to identify
mechanisms by which inhibitors affect host cell transcription patterns. We will also determine if the inhibitors
regulate the production of epithelial factors that modulate CD4+ T cell pro-asthmatic activity. Experiments
with PI and its structural analogs, and HRV, will be conducted in mice to test their in vivo anti-viral activity.
Additional mouse studies will use a house dust mite immunogen and HRV1B infection as a model for asthma
exacerbations. The efficacy of phospholipids as suppressors of asthma exacerbations will be critically tested
using the mouse model. From these studies we expect to identify important environmental promoters of
asthma exacerbation that work in combination with HRV. We also expect to identify epithelial transcriptomic
signatures and CD4+ T cell transcriptomic signatures and epigenetic landmarks that will be highly pr...

## Key facts

- **NIH application ID:** 10009452
- **Project number:** 5P01HL132821-04
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** Max A Seibold
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,786,716
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10009452

## Citation

> US National Institutes of Health, RePORTER application 10009452, Defining Molecular Phenotypes of Exacerbation Prone Asthmatics (5P01HL132821-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10009452. Licensed CC0.

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