This application for a K23 award proposes complementary research and training plans for Dr. Sharon Chung, a rheumatologist at the University of California, San Francisco. Dr. Chung is establishing herself as a translational investigator conducting patient-oriented genomic studies of systemic vasculitis. In this proposal, Dr. Chung will focus on granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis) as a potential model for other systemic vasculitides. The overall goal of the research plan is to broadly assess the contribution of three major biologic processes--genetic mutation, epigenetic dysregulation, and aberrant gene expression--to disease susceptibility and activity in GPA. In the proposed studies, Dr. Chung will utilize cutting-edge next-generation sequencing techniques and state-of-the-art DNA methylation arrays to identify these factors. Specifically, Dr. Chung will (1) perform exome sequencing to identify novel protein-influencing genetic variants associated with GPA disease susceptibility, (2) examine how DNA methylation, an epigenetic modification, of specific leukocyte subsets influences disease risk and activity using high-throughput methylation arrays, and (3) determine how gene expression patterns assessed via RNA-sequencing of specific leukocyte subsets change with disease activity. These studies, as well as structured didactic and tutorial experiences, will provide Dr. Chung essential training in (1) emerging genomic methodologies and fields of research, (2) advanced statistical techniques used to analyze sequence, methylation, and gene expression data, and (3) bioinformatic tools to organize, visualize, and process complex genetic datasets. To facilitate the research and training provided by this award, Dr. Chung has assembled an outstanding multidisciplinary mentoring team comprised of Dr. Lindsey Criswell (a rheumatologist conducting genetic epidemiology studies of lupus and rheumatoid arthritis), Dr. Pui-Yan Kwok (an expert in applying state-of-the-art genomic tools to search for genetic factors associated with complex human diseases), and Dr. Joseph Costello (a leading investigator of epigenetic and transcriptional influences on brain tumors). Drs. John Witte and Mark Segal, experts in analysis of sequence and methylation data, will serve as advisors and provide guidance in bioinformatics and statistical methods. The training obtained with this K23 award will enable Dr. Chung to achieve her long-term objective of becoming an independent investigator and leader in the field of vasculitis genomics. The findings from these studies will provide critical preliminary data supporting an R01 application to conduct larger, more comprehensive evaluations of sequence variation, epigenetic modifications, and transcriptional changes to better understand the pathogenesis of systemic vasculitis.
Granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis) is a potentially life-threatening, systemic vasculitis with current treatments that are untargeted and associated with significant toxicity. This study will identify genetic, epigenetic, and transcriptional factors contributing to GPA disease risk and activity, in order to clarify the biologic mechanisms causing disease. With an improved understanding of the factors causing disease, more targeted and less toxic therapies can be developed, thus improving the poor prognosis and long-term outcomes of GPA patients.