Chronic rhinosinusitis (CRS) causes profound loss of quality of life and over $10B of expense to the US healthcare system annually. Treatment options are primarily limited to corticosteroids, antibiotics and surgery. CRS is conventionally divided into two major forms, one without nasal polyp formation (CRSsNP), and one with nasal polyp formation (CRSwNP). A particularly severe form of CRSwNP is Aspirin Exacerbated Respiratory Disease (AERD). Patients with AERD suffer from both nasal polyposis and asthma, usually in severe forms. The fundamental hypothesis to be tested by this proposal is that a combination of defects in the immune barrier along with activation of inflammatory and structural cells drives pathogenesis in CRS and AERD. Secondary central goals of this proposal include advancement of our knowledge of pathogenesis of CRSwNP and AERD, development of a new microparticle (MP) based tool for diagnosis of AERD and assessment of the importance of hormones and cytokines in epithelial activation in CRS pathogenesis. We will use a combination of large, robust studies of patients undergoing surgery for CRS and cutting edge laboratory-based and bioinformatics approaches to study CRS pathogenic mechanisms. The proposed work is divided into three specific aims. In the first aim, we will test the hypothesis that epithelial-mesenchymal transition (EMT) is a hallmark feature of CRSwNP reflecting underlying endocrine disturbances and associates with severity and outcomes in CRSwNP. We will relate the extent of EMT in epithelial scrapings from CRSwNP, AERD and controls to disease endpoints to test our hypotheses that hormonal changes, Oncostatin M and Epiregulin play important roles in CRS- associated EMT and CRS pathogenesis. In the second aim, we will test the hypothesis that inflammatory leukocytes, structural cells and mast cells are activated in CRSwNP and AERD and contribute to symptoms and disease activity. We will use an innovative MP assay combined with flow cytometry and RNASeq (Drop-Seq) to assess activation of basophils, eosinophils, mast cells, platelets, endothelial cells and epithelial cells in controls and patients with CRSwNP or AERD. We will relate cell activation to disease severity assessed using CT, endoscopy, treatment history, questionnaires and tissue pathology. We will link inflammatory endpoints to EMT and important clinical endpoints. Finally, we will test the hypothesis that greater activation of eosinophils, basophils, mast cells and platelets explains the greater severity of disease in AERD.
In aim three, we will use the MP assay to identify patients with undiagnosed AERD among a large cohort of patients with CRSwNP and comorbid asthma. We will confirm or eliminate diagnosis of AERD with aspirin challenge to validate the MP test. These studies will advance knowledge of the mechanisms of pathogenesis of CRS and AERD and bring us closer to new diagnostics and therapeutic interventions.
Chronic rhinosinusitis (CRS) and aspirin-exacerbated respiratory disease (AERD) are diseases that cause severe impairment of breathing through the nose and into the lungs and lead many people to undergo surgery and take potent steroid drugs in order to breath. The research in this grant will use several recently developed techniques to test new ideas about what the core causes of CRS and AERD are, including the idea that changes in hormones and increased activation of inflammatory cells are responsible for disease. We have a collaboration of ENT surgeons, Allergists and Immunologists and will perform these studies in the operating rooms, in the clinics and in the laboratories at Northwestern University with the essential cooperation of volunteer patients.
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