Genetic basis of IBD susceptibility & steroid response

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Inflammatory bowel disease (IBD) is a common, chronic disorder of the gastrointestinal tract characterized by abdominal pain, diarrhea, growth disturbances, and general discomfort. Administration of glucocorticoids is one of the mainstays of treatment. However, the efficacy of glucocorticoids is highly variable, and adverse effects are common in affected individuals whose disease is glucocorticoid-dependent. The overall goal of this project is to determine whether variants in genes encoding mediators of immune response pathways directly affected by glucocorticoids influence susceptibility to IBD, as well as an affected individual's response to treatment with glucocorticoids. This goal will be accomplished by (1) characterizing the pattern of population genetic variation in each of 16 candidate genes encoding members of the NF-icB, MAPK/JNK/AP-1, and JAK/STAT signaling networks, and the human glucocorticoid receptor; and (2) testing for association between variants in these candidate genes and susceptibility to IBD and therapeutic response to glucocorticoids. Association studies will be performed in 2 different cohorts: (1) 552 affected-IBD cases of all ages including approximately 230 affected sib-pairs; and (2) 315 pediatric IBD trios (affected child plus parents). A five year mentored program is proposed that will incorporate both didactic and research training and will be guided by a well-established investigator at the University of Utah. Through an NIH-funded K30 award, the University of Utah's General Clinical Research Center provides a unique training program in clinical research focused on the inherited basis of human disease. This program incorporates access to resources-such as multiuser core facilities, large research centers at the University, and a designated clinical research unit in the University Hospital- with a specific mentored intensive research experience for maturing clinical investigators. The candidate will enroll in the K30 program. Thus the University of Utah provides an ideal environment for maximizing the potential of this study and the candidate.