Patient-Oriented Research Mentorship and Training in Upper Airway Allergic and Inflammatory Diseases - Project Summary/Abstract The cytokines IL-4, IL-5, and IL-13 are thought to be key effectors of airway inflammation, but remarkably little is known about either their global function within the respiratory tract or the potential consequences of their complete inhibition by newly available biologic drugs. The overall goal of the proposed research is to define the underlying human biology of IL-4Rα and IL-5R signaling in airway inflammation, both their role in driving type 2 inflammation and their role in counterregulating other systemic immune pathways. We will determine the cell-specific impacts of these cytokines within the respiratory tract and confirm the influence of IL-4Rα and IL-5R on the chronic inflammation of patients with chronic rhinosinusitis with nasal polyposis (CRSwNP), severe asthma, and aspirin-exacerbated respiratory disease (AERD). Further, given that some drugs now available to inhibit these pathways have poorly understood side effects like new-onset joint pain, we will establish the systemic immunologic consequences of inhibiting a receptor as widely expressed as IL-4Rα and will identify novel biomarkers to predict those immune responses. In three separate but interrelated projects, we aim to: 1. Define the cellular mechanism(s) of anti-IL-4Rα-induced therapeutic benefit in AERD with a prospective study of 8 weeks of dupilumab treatment. 2. Define the systemic immunologic consequences of IL-4Rα inhibition with dupilumab and determine which immunologic changes correlate with the development of arthralgias. 3. Characterize the functional significance of IL-5Rα on upper airway nasal plasma cells and epithelial cells, from patients with healthy sinus mucosa, CRSwNP, and AERD. These goals will be achieved using patient-oriented research (POR), as each of these aims involve patient interactions and longitudinal study visits to collect and verify clinical outcomes, and through the mentorship of the next generation of patient-oriented allergic disease investigators. The proposed studies and the clinical questions to be examined offer outstanding training opportunities for junior investigators interested in clinically relevant research in allergy and asthma. Dr. Tanya Laidlaw is a recognized investigator in the causes of CRSwNP and AERD and the candidate's many ongoing POR projects and collaborations, commitment to and track record of mentorship, along with the exceptional institutional resources, provide a first-rate environment for the development of junior investigators. Critically, this award will provide Dr. Laidlaw protected time for POR in airway inflammation and allergic respiratory disease to both refine her mentoring and leadership skills and expand her expertise to include predictive biomarker identification, pathway-level multi-omics analysis, and high dimensional data analyses.
