# A new mouse model of severe asthma

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $233,250

## Abstract

Project Summary
Severe asthma comprises ~10% of all asthma cases but accounts for a disproportionately high degree of
asthma health care costs and causes substantial decrements in quality of life for patients. Clinically, this form
of asthma is defined by inadequate symptom control despite treatment with high-dose inhaled corticosteroids
combined with a long-acting β2-agonist (LABA) or leukotriene modifier. Persistent airway obstruction,
increased urgent care utilization, and near-fatal events are also features of severe asthma. The “Type 2-high”
(T2-high) form of severe asthma is a common severe asthma sub-type that is characterized by sputum
eosinophilia, elevated fraction of exhaled nitric oxide, and increased serum periostin. While new, antibody-
based treatment approaches for T2-high asthma have come online, these treatment approaches are only
partially effective and do not sufficiently alleviate asthma symptoms and quality of life metrics. Thus, there is
still an unmet need for new therapeutics for severe Type 2-high asthma. To address this need, we sought to
create/identify a new model of severe T2-high asthma that could be used to identify and test new therapeutic
approaches. We identified a strain from the Collaborative Cross mouse genetics reference population, namely
CC011/UncJ (hereafter referred to as CC011), that develops extremely high levels of airway eosinophilia, total
and HDM-specific IgE, and airway hyper-responsiveness after repeated house dust mite (HDM) allergen
exposure (25 µg/treatment by intranasal administration, 3x/week for 5 weeks). Most impressively, CC011 mice
consistently died after HDM exposure during weeks 3-4 of treatment, whereas there were no deaths among
PBS treated CC011 mice or any other 30 CC strains tested. Importantly, steroid treatment did not ameliorate
eosinophilic airway inflammation in this strain. Thus, CC011 represents a new model of severe, T2-high
asthma. To further the utility of this of this model, the genetic and immunologic basis of this phenotype need to
be determined. In the first aim, we will identify which cell types and pathways are integrally involved in CC011’s
innate and adaptive immune responses to HDM. We will determine if allergic inflammation is T cell-dependent
and if CD4+ Th2 cell priming is augmented in CC011 mice compared to BALB/cJ mice. We will investigate if
airway epithelial cell-derived alarmins (IL-25, IL-33, TSLP, IL-1α/β) are increased in CC011 mice and whether
neutralization of these cytokines ameliorates allergic inflammation. Finally, we will determine if allergen-
induced expansion and activation of ILC2s are enhanced in CC011 mice. In the second aim, we will identify the
genetic loci that harbor CC011’s susceptibility alleles using a quantitative trait locus mapping approach, and
then leverage whole genome sequence data and gene expression data from CC011 and other strains to
identify candidate genes. These candidate genes will become the focus of future investig...

## Key facts

- **NIH application ID:** 10259944
- **Project number:** 1R21AI162084-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Samir Kelada
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $233,250
- **Award type:** 1
- **Project period:** 2021-05-19 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10259944

## Citation

> US National Institutes of Health, RePORTER application 10259944, A new mouse model of severe asthma (1R21AI162084-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10259944. Licensed CC0.

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