Genomic Approaches to Host-Pathogen Interactions

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DESCRIPTION (provided by applicant): The intestinal epithelia barrier and the mucosal immune system detect and respond to intestinal antigens. This response varies from tolerance to resident commensals an active immune response to pathogens. A better understanding of the interaction between intestinal microflora and the intestinal mucosa should provide insight into the pathogenesis of intestinal inflammation. The underlying hypotheses at work are 1) pathogens uniquely alter gene expression in the intestinal mucosa and specific receptors in the intestinal mucosa are responsible for initiating host cell responses 2) NF-kappaB activation functions as a nodal point for pathways activated by innate and adaptive immunity 3) In addition to eliciting transcriptional responses intestinal microbes induce dramatic changes in the actin cytoskeleton. The proposed research will focus on model systems familiar to our laboratory. As part of our preliminary studies for this proposal, we have established and tested an expression cloning strategy capable of identifying known and novel activators of pathogen responsive host transcription factors. To accomplish these goals, the specific aims of this proposal are: Specific Aim I: To identify signaling molecules that contribute to the host cell NF-kappaB response to bacteria. Specific Aim II: To delineate molecular pathways that mediate host cell actin cytoskeletal changes in response to bacteria. The long term goals of this research program is to identify proteins associated with and that influence immunity, inflammation and host resistance to intestinal inflammation.