DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE, lupus) is a chronic systemic autoimmune disease characterized by auto reactivity of B and T cells, production of autoantibodies and tissue deposition of immune complexes, resulting in organ damage. Disordered immunoregulation in SLE occurs in a genetic background involving lupus susceptibility genes. Hyperactivity and abnormal responses of B cells is at the center of SLE pathogenesis and leads to increased production of autoantibodies, failure of self tolerance mechanisms and inadequate clearing of immune complexes. microRNAs (miRNAs) emerged over the last decade as a conserved class of non-coding RNAs that regulates gene expression. Accumulating evidence underscores the importance of this pathway, whose tentacles control regulatory circuits in development, in normal physiologic processes and in disease state. Current evidence supports a key role for miRNAs in the development and function of the immune system and emerging evidence underscores the importance of this regulatory pathway in autoimmunity. However, the signaling pathways regulated by miRNAs in SLE remain largely unknown. Research in our lab focuses on the function of miRNAs in the tri-congenic mouse model B6.Sle123. Autoimmune disease in B6.Sle123 is characterized by autoantibodies, lymphosplenomegaly and glomerulonephritis, strongly resembling human lupus. We studied the expression of miRNAs in B6.Sle123 lymphocytes, at different time points in the course of twelve months, while the autoimmune disease of B6.Sle123 mice progresses from mild to severe. We demonstrated that expression of a set of miRNAs positively correlates with development and severity of severe lupus manifestations, such as kidney disease. Current therapies available for SLE are toxic and they are not targeting lupus-specific disordered mechanisms. The proposed research focuses on identifying miRNA-dependent signaling pathways that are uniquely affected in a mouse model of lupus, in which disease manifestations and disordered mechanisms overlap with those in human SLE. In our studies we will employ novel in vivo experimental methods combined with standard in vitro techniques. Our ultimate plan is to broaden our knowledge and understanding of miRNA function in lupus and to identify potential novel therapeutic targets in SLE.

PUBLIC HEALTH RELEVANCE: Results from basic, translational and clinical research underscore the importance of gene regulation mediated by microRNAs (miRNAs). miRNAs control pathways important in normal development and normal cellular functions, however they also play instrumental roles in disease mechanisms. Although current evidence supports a critical role for miRNAs in the development and function of the immune system, very little is known about the function of miRNAs in autoimmune diseases and in particular in Systemic Lupus Erythematosus (SLE). We propose to identify and characterize the molecular pathways that are regulated by miRNAs in lupus, using a genetic tricongenic mouse lupus model that recapitulates many seroligcal and clinical manifestations of human disease. Our long term goal is to identify disordered molecular pathways in lupus, which could potentially serve as novel, disease specific, therapeutic targets. We foresee that results of the studies described in this proposal will be of considerable interest to a broad spectrum of biomedical disciplines