Nasal Microbiome and Host Immunity in Granulomatosis with Polyangiitis

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PROJECT SUMMARY Dr. Rhee's long-term career goal is to become an independent investigator in patient-oriented clinical and translational research dedicated to improving the lives of patients with vasculitis. She will build upon her current skills in clinical epidemiology and gain critical experience in the conduct of prospective patient-oriented research, use of deep sequencing methods, and implementation of bioinformatics and advanced epidemiologic methods. Through the K23 award, the execution of the proposed study, and career development activities, Dr. Rhee will acquire the skills and training needed to make important scientific advances in rheumatology. Granulomatosis with polyangiitis (GPA; Wegener's) is a systemic granulomatous vasculitis which often affects the upper respiratory tract and frequently relapses. Prior studies demonstrated that microbes in the nares are associated with relapse in GPA but these studies relied on culture-dependent approaches. Advances in high- throughput sequencing and the development of new tools for analyzing metagenomic data now allow for a better understanding of the complex relationship between the dynamic community of microbes that occupy our mucosal tissues and the host's immune system. We hypothesize that patients with GPA have greater dysbiosis (disruption in indigenous microbiota) in the nares compared to controls and that greater dysbiosis is associated with disease activity in GPA, mediated by an increase in neutrophil activity (a key pathogenic cell in GPA). The Specific Aims are: 1) compare the nasal microbiome between patients with GPA versus controls, and 2) examine longitudinal changes in the nasal microbial composition of patients with GPA and the association of these changes with gene expression profiles in the nasal epithelium and clinical outcomes. A better understanding of the complex microbial interactions with the mucosal immune system in GPA can advance our understanding of the pathophysiology of GPA, help predict future relapse, and inform the development of novel therapeutics. Findings from this study will be applied to applications for funding (R01 and others) to perform large-scale studies of host-microbe interactions in GPA. In order to successfully execute the proposed study and develop a career studying host-microbe interactions in rheumatic diseases, Dr. Rhee and her mentors have formed a comprehensive career development plan which draws upon the expertise of her mentors and the rich resources available at Penn. Dr. Rhee will engage in formal didactics including completion of the Biomedical Informatics Certificate Program, participate in relevant seminars and conferences, and devote at least 75% of her effort to research. Guided by expert mentors and collaborators, the research and training activities outlined in this application will enable Dr. Rhee to grow from an observational epidemiologist into an independent patient-oriented clinical and translational researcher, equipping her with a much larger set of skills to answer important and novel questions about vasculitis.