This program project grant application focuses on the use of DNA micro array (gene chip) technology to detect differential expression of genes in children with pediatric arthritis. It builds on the existing resources and provides strong interactions and synergism with the Cincinnati Rheumatic Diseases Core Center (P30) grants in existence within the applicants' center. Rapid advances in biotechnology, including the human genome project, the advent of high through put micro arrays that contain nearly all genes in the human genome, and statistical computing power have come together to create an unprecedented opportunity to refine the diagnosis, treatment, and understanding of the pathophysiologic mechanisms involved in pediatric rheumatic diseases. Four projects are proposed. Project by Glass focuses on the recognition of disease specific gene expression profiles in peripheral blood from inception cohorts of children with either poly or pauciarticular onset juvenile rheumatoid arthritis (JRA). Prospective follow-up of these patients will reveal how gene expression patterns change with disease evolution and therapy and will provide insights into varying pathophysiological mechanisms between the two disease subtypes. Project by Hirsch will perform a comprehensive functional genomic analysis of synovium in JRA, and elucidate the molecular pathways responsible for the aggressive behavior of fibroblasts in arthritic synovium. Project by Colbert focuses on juvenile spondyloarthropathies (JSpA) and aims to determine whether expression profiles distinguish JSpA from other forms of pediatric arthritis and controls. Project by Grom will determine if expression profiles in early disease can distinguish patients with systemic JRA (sJRA) who progress to an aggressive form of articular disease from those that do not, and determine the extent of NK dysfunction early and late in the disease. In addition, expression patterns among patients with sJRA who have acute macrophage activation syndrome (MAS) will be compared to patterns obtained after resolution of MAS and among those with a history of MAS. An Administrative Unit will in conjunction with the MCRC Methods Core manage the prospective clinical studies will assure proper collection and processing of demographic and clinical phenotype data. The Administrative Unit will also provide leadership and evaluate program progress. The Tissue Core, an extension of the P30 Tissue Repository will handle biological specimens from initial acquisition through to the release to the Affymetrix Core. An Informatics Corelis proposed to manage and analyze the data in conjunction with project staff and develop a web-enabled national level genomic database.
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