The Chronic Rhinosinusitis Integrative Studies Program 2 (CRISP2) is an integrated program of epidemiologists, otolaryngologists, allergists and immunologists in which highly collaborative studies are proposed to better understand the molecular and cellular mechanisms of disease heterogeneity and how these mechanisms translate into clinical phenotypes, natural history and long term outcomes. The program focuses on CRS without nasal polyps (CRSsNP), a highly prevalent and yet obscure phenotype from the standpoint of current understanding. Another focus of CRISP2 is to critically evaluate the mechanisms and consequences of comorbid conditions in which patients have both CRS and lung disease such as asthma or bronchiectasis. To achieve these goals, the investigators on the CRISP2 study team have innovated new assays and approaches to cutting edge studies of pathogenesis and epidemiology and, most importantly, have merged these two disciplines to relate mechanisms to symptoms, severity, history and outcomes of CRS. Epithelial barrier dysfunction, induced by injury and inflammation, can lead to barrier loss, which activates epithelial-mesenchymal transition (EMT) during the epithelial repair process. Project 1 investigates the mechanisms of barrier dysfunction and its role in CRS severity and outcomes. Another topic follows our findings that tissue hyperplasia is driven by deposition of cross-linked fibrin. Linking barrier loss and fibrin deposition are preliminary data suggesting that both EMT and fibrin deposition are driven by type 2 inflammation. Project 1 will be the first to study mechanisms of hyperplastic changes confined to the sinuses in a newly defined phenotype of CRS (CRSsNP-HP). Barrier dysfunction and fibrin deposition will be related to immunological endotype and their influence on phenotype, comorbidity and outcomes assessed. Studies in aim one test the hypothesis that loss of barrier integrity and function is induced by oncostatin M (OSM), thyroid hormone and epiregulin (EREG), and associates with type 2 inflammation. Epithelial EMT will be monitored with a novel microparticle-based assay applicable to large numbers of nasal lavage fluids from patient cohorts at NU (tertiary care) and Geisinger (primary care). Single cell RNA-Seq studies will evaluate epithelial differentiation and EMT in samples from patients with CRS. The second aim tests the hypothesis that type 2 inflammation promotes fibrin deposition and formation of hyperplastic tissue, based on results implicating loss of fibrinolytic pathways and increased levels of fibrogenic mediators. We predict that biochemical measurement of tissue fibrin will correlate with endotype and hyperplastic tissue changes (polyps > hyperplastic disease >> non-polypoid disease) and will monitor the coagulation system, fibrinolysis and fibrin deposition in patients with defined endotypes to test this hypothesis. The third aim tests the hypothesis that autoimmune antiphospho...