Our long-range objective is to understand the etiology of systemic lupus erythematosus(SLE). Our present work has sought to provide a comprehensive picture of the different antigen-antibody systems that involve ribonucleoproteins in patients with this disease. The outcome has been the development of the hypothesis that specific nucleoproteins, especially the U1 snRNP, the nucleosome, and the Ro particle, actively elicit and possibly propagate autoimmune responses in this disease. To develop this hypothesis further, we are now concentrating our efforts to study the structure and biologic function of the autoantigenic Ku protein--a newly discovered chromatin component which we hypothesize plays a role in DNA repair or transposition--and the Ro particle--which is a central focus of autoimmune responses in patients with SLE. Work on the Ku protein will seek to establish its structure and biologic function. We will use cloning and standard biochemical approaches to characterize this protein structurally and to identify its autoantigenic epitopes. In addition, we will seek to identify its function using a variety of biological assay systems. Finally we will develop a new ELISA for measurement of anti-Ku antibodies in clinical studies using recombinant Ku protein as antigen. Work on the Ro particle will concentrate on developing specific probes--including monoclonal antibodies--that recognize it, devising a method for reconstituting it in vitro, and determining its location in cells. In addition, we will compare patient sera with immunized animal sera in terms of specific Ro protein epitopes recognized by each. This work will provide new information about the structure of the Ku protein and the Ro particle. It may succeed in defining the biological function of these newly recognized cellular elements. Information about the structure and function of the Ku protein and the Ro particle could help us understand why certain nucleoproteins become targets for selected autoimmune responses in patients with SLE.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Yale University
Schools of Medicine
New Haven
United States
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