Genetic and Longitudinal Analysis of Airway Remodeling

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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, providing a significant foundation for identifying new targeted therapeutics for asthma.!