GENETIC BASIS OF IBD SUSCEPTIBILITY AND STEROID RESPONSE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Experimental data from both animal models and studies in humans demonstrate that 1) tumor necrosis factor alpha (TNFalpha), 2) the Th1/Th2 cytokine response, and 3) the resistance of activated lymphocytes to apoptosis play important roles in the pathogenesis of irritable bowel disease (IBD). Effective TNFalpha signaling, Th1/Th2 lymphocyte differentiation, and the resistance of activated lymphocytes to apoptosis require the NF-kappaB, MAPK/JNK/AP-1, and JAK/STAT signaling networks, and experimental evidence suggests that glucocorticoids directly influence these pathways. We hypothesize that variation in the genes encoding the pivotal mediators of these signaling networks are associated with susceptibility to IBD and therapeutic response to glucocorticoids. To address this hypothesis, we propose the following specific aims: 1.1. Characterize diversity in genes encoding the human glucocorticoid receptor, and members of the NF-kapppaB, MAPK/JNK/AP-1, and JAK/STAT signaling networks. 1.2 Test for association between genetic variants in candidate genes and susceptibility to IBD. 1.3. Test for association between candidate polymorphisms and the response to glucocorticoids in patients with IBD.