Airway Structural Cells and Corticosteroid Resistance in Asthma

PROJECT DESCRIPTION Severe asthma is characterized by resistance or insensitivity to corticosteroids leading to more frequent asthma symptoms, exacerbations, and hospitalizations than individuals with mild asthma. Type 2 inflammation has a central role in asthma pathogenesis, however little is known about how it contributes to corticosteroid insensitivity. Cytokines, IL-4 and IL-13, are increased in type 2 asthma, promote airway smooth muscle cells (ASM) dysfunction, and contribute to airway hyperresponsiveness and airflow obstruction. Although the effects of IL-4 and IL-13 are known, there remains a need to understand how they modulate gene expression and corticosteroid sensitivity in ASM. We hypothesize that combined exposure to IL-4 and IL-13 induces corticosteroid insensitivity in ASM. In this supplement, we will test this hypothesis in 2 Specific Aims: (1) Determine the combined effects of IL-4 and IL-13 on gene expression and chromatin accessibility in human ASM; and (2) Determine the role of IL-4 receptor-α in a mouse model of severe allergic airway inflammation. Studies in Aim 1 will explore effects of corticosteroids, IL-4, and IL-13 on gene expression and chromatin accessibility using RNA-seq and ATAC-seq in human ASM. In Aim 2, we will examine the role of IL-4Rα in a mouse model of severe allergic airway inflammation that exhibits corticosteroid insensitivity. While within the scope of the parent R01, the supplement will provide support for a graduate student who will receive training in gene regulation and asthma pathogenesis. The proposed research is accompanied with a comprehensive mentoring plan that will enable the student to receive scientific and professional training towards a career in biomedical research. Overall, these novel studies will help improve the understanding of underlying mechanisms in severe asthma while also facilitating the development of an aspiring biomedical scientist.