Juvenile rheumatoid arthritis (JRA) is one of the most common chronic conditions of children affecting approximately 50,000 children in the U.S. The etiology and pathogenesis of JRA is complex, though there is clearly a genetic component. Associations between the genes of the major histocompatibility complex and susceptibility to JRA are well established, though identification of causal genetic variants, much less translation to improve clinical practice has not been forthcoming. Over the last decade, direct and indirect evidence has pointed to a role of activated T-cells, particularly of the Th1 phenotype in the pathogenesis of JRA. The goal of this project is to determine whether genetic variation in genes encoding T-cell regulatory molecules contributes to variation in JRA susceptibility, pathogenesis and treatment outcome. This will be accomplished via two specific aims. 1. Analyze genetic diversity in genes encoding ligand-receptor pairs involved in T-cell regulation. 2. Test for association and linkage between the genetic variants identified and susceptibility to JRA and or/variable expressivity of JRA. These studies will be conducted using 3 different cohorts representing the largest collection of JRA patients in the U.S.: (1)140 sibpairs with JRA (2) 500 singletons with JRA and their parents and (3) cases newly ascertained from a registry of more than 650 JRA patients living in the Intermountain West. A five year mentored program is proposed that will incorporate both didactic and research training and will be guided by two established scientists at the University of Utah. Through a NIH funded K30 award, the University of Utah General Clinical Research Center provides a unique didactic program of training in clinical research focused on the inherited basis of human disease. This program incorporates access to resources such as multi-user core facilities, large research centers at the University, and a designated unit in the University Hospital, with specific mentored intensive research experience for maturing clinical investigators. Thus, the University of Utah provides an ideal environment for maximizing the potential of this study and this applicant.
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