# Genetic and Longitudinal Analysis of Airway Remodeling

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $33,903

## Abstract

ABSTRACT
 Asthma is a chronic lung condition that causes airway narrowing and hyperresponsiveness in over 25
million Americans. Despite available inhaled corticosteroid treatments for asthma, significant unmet therapeutic
needs remain. Changes in the cellular and tissue composition of the airways, referred to as airway remodeling,
are predicted to influence reduced lung function in asthmatics. These reductions cannot be fully resolved with
available therapeutics and can lead to mucus occlusion of the airways seen in fatal asthma attacks. Although
numerous genetic and environmental factors contribute to asthma risk and severity, identifying the drivers of
airway remodeling remains challenging due to the inability to sample lung tissue from a large number of
affected individuals and track remodeling over time. Elucidating the molecular regulators of airway remodeling
is a necessary step toward a more comprehensive understanding of asthma pathogenesis required to design
effective therapeutics.
 This project will interrogate the genetic and transcriptional regulation of airway remodeling in a chronic
allergen-induced mouse model of allergic airway disease. These analyses will robustly define the relationships
between remodeling phenotypes, identify novel therapeutic targets, and track remodeling development and
progression. Upon chronic exposure to house dust mite (HDM) allergen, mice develop features of airway
remodeling that mirror human disease, including goblet cell metaplasia, subepithelial fibrosis, and smooth
muscle thickening. I will investigate the mechanisms underlying these remodeling phenotypes through an
unbiased genome-wide approach with the Collaborative Cross (CC) mouse population. The CC is a panel of
recombinant inbred lines where the genome of each line represents a unique mosaic of eight founder strains
including five classical inbred and three wild-derived strains varying by 45 million single nucleotide
polymorphisms. This genetic variation results in high phenotypic variability across strains, making it possible to
make associations between phenotypic and genotypic variation, in addition to observing strains with novel
phenotypes. I will quantify airway remodeling phenotypes in 30 CC strains chronically treated with HDM and
estimate the contribution of genetic variation to remodeling, an important step in better understanding airway
remodeling drivers that has not yet been possible in humans. Furthermore, I will perform whole transcriptome
sequencing of airway tissue and use bioinformatic approaches to identify candidate transcriptional regulators of
airway remodeling phenotypes with a specific focus on mucus hypersecretion. These candidate regulators and
other genes will be evaluated in a time course of chronic HDM exposure that tracks the initiation and
progression of remodeling. In summary, the results of this proposal will further our understanding of airway
remodeling mechanisms and how remodeling is developed over time, pr...

## Key facts

- **NIH application ID:** 9981808
- **Project number:** 5F31HL143853-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Lauren Donoghue
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,903
- **Award type:** 5
- **Project period:** 2018-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981808

## Citation

> US National Institutes of Health, RePORTER application 9981808, Genetic and Longitudinal Analysis of Airway Remodeling (5F31HL143853-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9981808. Licensed CC0.

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