DESCRIPTION (provided by applicant): This is a NIH Mentored Clinical Scientist Development Award (K08) application for Dr. Shaun Jackson, an acting Assistant Professor in the Department of Pediatrics at the University of Washington (UW). Dr. Jackson completed combined clinical training in Pediatric Nephrology and Pediatric Rheumatology and has a clinical and research interest in systemic autoimmune diseases, in particular systemic lupus erythematosus (SLE). His long-term career goal is establish himself as an independently-funded, clinician-scientist focusing on the B cell- intrinsic mechanisms promoting development of humoral autoimmunity. To achieve this goal, Dr. Jackson is requesting NIH K08 support for additional training and mentorship in the following specific areas: (1) immune mechanisms underlying B cell activation by inflammatory cytokines; (2) testing of targeted kinase inhibitors in murine autoimmune models; (3) mentorship in effective lab and research personnel management; (4) attendance of scientific conferences and career development seminars; and, (5) development of an independent research focus and transition to scientific independence. As his primary mentor, Dr. Jackson has selected Dr. David Rawlings (UW/Seattle Children's Research Institute - SCRI), a leading expert in B cell biology, with a research focus into how dysregulated signaling impacts B cell function. To oversee his training, Dr. Jackson has assembled an advisory committee consisting of: his primary mentor Dr. Rawlings; Dr. Keith Elkon (Professor, UW Rheumatology), a leader in immune mechanisms underlying lupus pathogenesis; Dr. Mohammed Oukka (Assoc. Prof, UW/SCRI), an immunologist with specific expertise in cytokine biology; and, Dr. Troy Torgerson (Assoc. prof, UW/SCRI), an expert in primary immunodeficiency and TREG biology. Dr. Jackson's research during the period of career development support will focus on B cell-intrinsic mechanisms and novel B cell-targeted therapies in murine lupus. Despite tolerance mechanisms, autoreactive B cells are known to enter the mature B cell compartment in healthy individuals. To study the mechanisms promoting peripheral activation of autoreactive B cells in SLE, Dr. Jackson will take advantage of a novel B cell-driven murine lupus model developed in the Rawlings' laboratory. Dr. Jackson's preliminary data emphasize the utility of this model by providing the first demonstration that B cell (and not myeloid) TLR7 and TLR9 signals impact the autoantibody repertoire and immune-complex glomerulonephritis (Jackson SW, et al. Manuscript submitted). In the current application, Dr. Jackson proposes further mechanistic studies into how autoreactive B cells are initially activated, focusing on: Specific Aim 1) how the pro-inflammatory cytokine interferon gamma (IFN-γ) promotes B cell activation, germinal center formation and autoantibody class-switch recombination; Specific Aim 2) the B cell-intrinsic roles for type 1 interferon in promoting humoral autoimmunity. Further, based on the observation that TLR7 and TLR9 signals drive B cell activation and autoantibody production, Dr. Jackson will test the therapeutic efficacy of small molecule inhibitors targeting B cell receptor (BCR) and Toll-like receptor (TLR) signaling pathways (Specific Aim 3). These studies hold the promise of translating mechanistic insights into B cell-intrinsic signals promoting autoreactive B cell activation into novel clinical therapies for SLE. Further, it is anticipated that these studies wil provide the preliminary data and research publications necessary to support a successful R01 application prior the end of career development support.

PUBLIC HEALTH RELEVANCE: Autoantibody-producing B cells are known to play a central role in the pathogenesis of systemic lupus erythematosus (SLE), but the specific mechanisms whereby B cells are initially activated to produce autoantibodies are not known. Utilizing a novel murine lupus model, our prior data demonstrate that B cell Toll- like receptor (TLR) activation promotes anti-nuclear antibody formation and autoimmune glomerulonephritis. In the current proposal, we will perform additional studies addressing how autoimmune B cell responses are impacted by interferon gamma gamma (IFN-γ) and type 1 interferon, two important cytokines effectors implicated in lupus pathogenesis. In addition, we will test the efficacy of candidate small molecule inhibitors targeting B cell receptor (BCR) and toll-like receptor (TLR) signaling pathways as novel therapies for SLE.