Novel role of alpha-1 antitrypsin in monocyte-driven disease activity in ANCA-associated vasculitis - PROJECT SUMMARY Candidate: Lynn Fussner, MD, is an early stage investigator in the Division of Pulmonary, Critical Care, and Sleep Medicine at The Ohio State University who is dedicated to improving care of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Dr. Fussner’s patient-oriented clinical and translational research in AAV has included study of patient outcomes and single biomarkers for predicting relapses. With this proposal, Dr. Fussner’s goals are to expand her skillset to include advanced statistical modeling and bioinformatics coupled with understanding of immunological methods to investigate novel mechanisms underlying the pathogenesis of AAV, and leverage markers and modifiers of those mechanisms for personalized management of these rare diseases. Career Development Plan: To achieve these goals, Dr. Fussner and her primary mentor, Dr. Kymberly Gowdy, MS, PhD, have outlined a comprehensive career development plan incorporating coursework and experiential learning in immunology, biostatistics, bioinformatics, and strategies for study design in rare diseases. Central to this plan is strong mentorship from Dr. Gowdy (expert in translational innate immunity in lung and vascular diseases), Ohio State co-mentors, Dr. Elliott Crouser (pulmonary/critical care physician-scientist, monocytes as biomarkers) and Dr. Guy Brock (biostatistics/bioinformatics), and international leaders in vasculitis, Drs. Ulrich Specks (pulmonary physician- scientist at Mayo Clinic) and Peter Merkel (rheumatology physician-scientist at Penn, Director of the Vasculitis Clinical Research Consortium (VCRC)). Environment: Ohio State’s research environment couples a large patient population with well-funded multidisciplinary clinical, translational, and basic research infrastructure. This includes the Center for Clinical and Translational Science and the Davis Heart and Lung Research Institute. Research: Dr. Fussner will investigate the role of alpha-1 antitrypsin (A1AT) and monocytes as drivers and markers of AAV. A1AT is the primary inhibitor of proteinase 3, which is the predominant target of ANCAs in the western hemisphere. Patients with A1AT deficiency alleles have increased risk of AAV, and our preliminary data indicate that A1AT genotype impacts the clinical phenotype of AAV. Dr. Fussner’s specific aims are: Aim 1: Determine whether A1AT levels, alone or in combination with ANCA levels and monocyte inflammatory markers, predict disease activity and clinical phenotype of AAV. Aim 2: Determine whether ANCA- induced monocyte signatures predict clinical features of AAV and evaluate the impact of exogenous A1AT. Dr. Fussner will utilize clinical data and samples from two cohorts: (i) patients with AAV with and without A1AT deficiency alleles from the VCRC, the world’s largest vasculitis biorepository, and (ii) a clinical trial cohort of patients with relapsing AAV. Patient total and functional A1AT levels, and ANCA-induced monocyte responses will be analyzed for prediction of disease activity and specific manifestations of AAV. These studies will enhance understanding of AAV pathogenesis and identify new biomarkers and safer treatment strategies in AAV.
