Project Summary This project summary pertains to the Supplement. Rhinosinusitis (RS) is one of the most prevalent airway diseases, effecting approximately 15% of the U.S population. With symptoms of sinonasal mucus hypersecretion and plugging, severe facial pain and breathing difficulties, RS significantly affects both quality of life and socioeconomic burden. Despite these dire outcomes, the etiology of RS is completely unknown, severely hampering the development of preventative or curative treatments. In the parent grant, we investigate how aberrant patterning of the nasal submucosal glands (SMGs), may be causative for chronic RS (CRS, > 12 weeks). Based on the high penetrance of CRS in patients with mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene (Cystic Fibrosis) and studies showing aberrant SMG morphology and function are common to this disease, this proposal tests the hypothesis that dysfunction in CFTR leads to aberrant SMG patterning and thus, CRS. This hypothesis will be tested via three specific aims. (1) Define cell identities, lineage dynamics and cell-cell signaling networks during SMG development. In this Aim, transcriptomic techniques and quantitative measures of morphological changes will be employed to uncover processes governing human SMG development, which can then be utilized to delineate mechanisms of disease SMG patterning. (2) Elucidate CFTR dysfunction in SMGs as an underlying cause of CRS. This Aim will use the murine mouse model to test the hypothesis that mis- regulation in CFTR is a cause of tissue remodeling and CRS. (3) Identify molecular and cellular signatures of SMG remodeling in human adult CRS. This final aim will examine morphological and transcriptomic gland phenotypes common to healthy, eosinophilic CRS without polyps, and eosinophilic CRS with nasal polyps, providing insight into alterations in gland structure and function, and thus contribution to different CRS pathologies. In this Diversity Supplement application, we build on our subsequent studies that have established the emergence of nasal ionocytes during early SMG morphogenesis, with an enrichment of these cells in SMG ducts. We confirm that Cftr expression is highly expressed in embryonic ionocytes and epithelial specific deletion of Cftr significantly reduces ionocyte identity regulator genes. To this end, we hypothesize that CFTR regulates ionocyte differentiation and SMG development. To test this, we will build on our AIM 1 and AIM 2 of the parent grant and scrutinize the role of CFTR in ionocyte specification and airway SMG signaling mechanisms, at a single cell resolution. Outcomes will determine how CFTR mediates ionocyte emergence and how this contributes to aberrant SMG morphogenesis.