Inflammatory bowel disease is a major cause of suffering in the developed world. Pro-inflammatory cytokines, chemokines and eicosanoids are present in high concentrations in inflammatory bowel disease. Many of these inflammatory mediators can be positively regulated by nuclear factor kappa B (NF-kappaB) family of transcription factors. However, it is not known if NF-kappaB activation in vivo promotes intestinal inflammation, or plays a role in protective host responses by inhibiting apoptosis in the inflamed intestine. Our central hypothesis is that NF-kappaB activation in cells of the innate immune system regulates intestinal inflammation and host responses to inflammation in vivo. This hypothesis will be tested by studying the key molecule that activates NF-kappaB, inhibitory kappa B kinase beta (IKKbeta). Studies in specific aim 1 will generate and characterize a transgenic mouse line that expresses cre recombinase exclusively in intestinal epithelial cells. Studies in specific aim 2 will determine the role of IKKbeta in the activation of NF-kappa B in cells of the mucosal innate immune system. Two conditional knockout mouse strains will be generated by cre/loxP-mediated recombinant of the IKKbeta locus: a) Mice that express cre recombinase in intestinal epithelial cells will be crossed with mice bearing a loxP-flanked IKKbeta locus to produce intestinal epithelial IKKbeta knockout mice; b) Existing mice that express cre recombinase in macrophages and neutrophils will be crossed with mice bearing a loxP-flanked IKKbeta locus to produce macrophage and neutrophil IKKbeta knockout mice. Studies in specific aim 3 will determine the role of NF-kappa B activation in the pathogenesis of intestinal inflammation by analzing the course of colitis induced by feeding dextran sulfatesodium to mice that lack IKKbeta in intestinal epithelial cells or in macrophages and neutrophils. The mentored clinical Scientist Development Award will provide me with essential resources with which to perform this research. I will acquire the theoretical and experimental skills to launch a productive independent investigate career with the assistance of this award and of my institution, the Mayo Foundation for Medical Education and Research.
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