Asthma affects ~300 million people and causes ~250,000 deaths annually. The long-term overall vision of our research program is that fundamental insights into the biology of the airway epithelium will allow us to better understand asthma and other airway diseases and provide a firm foundation for developing new approaches to prevention, cure, or treatment of these diseases.
The concept that the airway epithelium plays a central role in asthma pathogenesis represents a relatively recent paradigm shift. We showed that direct effects of the type 2 cytokine IL-13 on resident airway cells were sufficient to induce airway hyperreactivity (AHR) and mucus overproduction. Our most important early contribution was the demonstration that IL-13-driven activation of the transcription factor (TF) STAT6 in airway epithelial cells causes AHR and mucus overproduction in mice. More recently, our studies of primary human bronchial epithelial (HBE) cells showed that IL-13 induces changes in expression, organization, and function of airway mucus glycoproteins (MUC5AC and MUC5B mucins). These changes lead to attachment (tethering) of mucus to the epithelium, prevent normal mucus clearance, and promote formation of obstructive mucus plugs that are a prominent feature of fatal asthma.
IL-13 stimulation blocks mucociliary transport. Images show fluorescent microparticles on top of mucus produced by primary human bronchial epithelial cells in culture.
Completed and ongoing studies in the lab are intended to help reach a deeper understanding of the molecular mechanisms underlying airway epithelial dysfunction in asthma. We study the mechanisms of gene regulation in the airway epithelium and determine the contributions of specific gene expression changes to changes in airway epithelial function. We use a variety of approaches from cell and molecular biology, genomics, and computational biology. We have adapted powerful new methods, including single cell RNA-seq (scRNA-seq), ChIP-seq, and CRISPR, for use with HBE cells as well as with cells obtained directly from individuals with asthma. We collaborate extensively with experts in asthma clinical studies, genetics and genomics, and computational biology.