Linking Mechanism to Outcome in Airway Inflammation and Remodeling - PROJECT SUMMARY Chronic rhinosinusitis (CRS) and asthma are common chronic inflammatory diseases that cause substantial morbidity and account for > 50 billion dollars a year in healthcare costs. Barrier epithelial cells play a central role in the initiation and persistence of each disease. Despite advances in sequencing, and growing databases of respiratory epithelial gene expression, we have not yet translated our knowledge of epithelial biology and gene expression into effective therapies or prevention strategies for most patients. Moreover, there are few centers that can train investigators in immunology, epithelial biology, computational approaches, and patient-oriented research (POR) to advance this field. The overall goals of this proposal are: 1) to develop my computational skills to make fundamental observations that inform the treatment and prevention of airway diseases, and 2) to train the next generation of patient-oriented researchers to do the same. In the research plan, I test 3 epithelial-centric hypotheses. The first hypothesis proposes that epithelial metabolic reprogramming underlies immune and barrier dysfunction in CRS with nasal polyps (CRSwNP). The second hypothesis proposes that IL-4/13 alters the basal cell (BC) epigenome in patients with CRSwNP and aspirin-exacerbated respiratory disease (AERD) in an irreversible manner that prevents normal BC differentiation and instead promotes BC expansion and inflammation. The third hypothesis proposes a novel mechanism of epithelial mesenchymal transition in CRSwNP. The proposals use cutting-edge omics technologies, providing a great opportunity for mentoring junior investigators in POR relevant to airway diseases. I have a strong record of accomplishment in mechanistic and patient-oriented research, and a track record of commitment to mentoring. However, the K24 mechanism will allow me to expand the number of trainees I can mentor, facilitate their training in POR and computational biology, and establish an immunogenomic workshop for trainees to develop their skills, as detailed in the mentoring plan. Additionally, the K24 mechanism will allow me to expand my own training in computational biology and machine learning to support the work of trainees in this rapidly changing field. This plan, in combination with the outstanding trainees, collaborators, and institutional environment in the Allergy and Clinical Immunology (ACI) Division at Brigham and Women’s Hospital will ensure an increased number of POR researchers in this field.
