Initiators, biomarkers and mechanisms of epithelial dysfunction and immune pathogenesis in chronic rhinosinusitis and aspirin exacerbated respiratory disease (AERD) - PROJECT SUMMARY
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.
