Project 2. Basal Cell Dysplasia in Type 2 Immunopathology

Project 2 Summary/Abstract Basal epithelial cells are the stem-like progenitor cells that give rise to all differentiated epithelial cell subsets. In addition to their progenitor function, they produce pro-inflammatory molecules including interleukin-33 (IL- 33) and thymic stromal lymphopoietin (TSLP), implicated in the pathobiology of type 2 (T2) inflammatory diseases such as eczema, food allergy, eosinophilic esophagitis, asthma, and nasal polyposis. Our group recently reported that basal cells from patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) are dysplastic, fail to differentiate into normal respiratory epithelial cells, and upregulate the capacity to generate proinflammatory molecules. These abnormalities are associated with an aberrant metabolic program. The goal of this research plan is to: 1) define how basal cell metabolism regulates their stem and proinflammatory functions, 2) determine how basal cell metabolism is altered in the sinonasal tissue of patients with different types of chronic rhinosinusitis, and 3) determine whether therapeutic inhibition of IL-4Rα will restore the metabolic, transcriptional, and epigenetic changes seen in basal cells in a severe CRSwNP subtype, aspirin- exacerbated respiratory disease.