Molecular mechanisms of the impact of Fli-1 on lupus

Medical University Of South Carolina, Charleston SC

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Abstract

DESCRIPTION (provided by applicant): Molecular mechanisms of the impact of Fli-1 on lupus Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by arthritis, vasculitis, immune complex glomerulonephritis and infiltration of inflammation cells into the glomeruli. Pathogenesis of SLE is not fully understood although much progress has been made. Renal disease is the major cause of morbidity and mortality. Previous studies indicate that overexpression of transcriptional factor Fli-1 plays an important role in disease development in murine models of lupus and likely in human SLE. Two to three-fold transgenic overexpression of Fli-1 in normal mice results in the development of a lupus-like disease. Active lupus patients have higher Fli-1 mRNA in peripheral lymphocytes compared with normal controls. We have found that genetic reduction of Fli-1 expression in both MRL/lpr mice and NZM2410 mice, murine lupus models, significantly prolonged survival, decreased autoantibody production, and decreased renal pathologic proliferative changes. Our hypothesis based on our preliminary data is that Fli-1 play a critical role in inflammatory cytokine and chemokine production in kidney and activation of Toll-like receptors (TLRs) in the progression of lupus glomerulonephritis. We propose here to further defining the molecular mechanisms of the impact of Fli-1 on lupus disease development. The following specific aims are proposed to address this hypothesis: Aim 1. Determine the role of Fli-1 in chemokine-driven leukocyte recruitment and activation during renal disease development. Aim 2. Define the role of Fli-1 in TLR path way and kidney injury. Aim 3. Determine the molecular mechanism whereby Fli-1 affects glomerulonephritis. These novel studies of the impact of Fli-1 on murine lupus will likely identify new pathways of disease pathogenesis applicable to human lupus and hold promise for the development of new therapeutic agents.