Rodent models of chronic intestinal inflammation provide powerful tools to investigate the pathogenesis of inflammatory bowel diseases (IBD). Spontaneous gene mutations, targeted deletion or overexpression of specific genes in mice demonstrate quite convincingly that genetically-determined immunoregulatory abnormalities can lead to chronic intestinal and systemic inflammation. Additionally, gnotobiotic studies firmly incriminate resident luminal bacteria as etiologic agents. However, mechanisms of initiation and regulation of this inflammatory response remain unclear, particularly in regard to the nature of chronic antigenic stimulation and the mechanisms by which bacteria induce inflammation. The long-term goal of this proposal is to identify specific environmental stimuli which initiate and perpetuate intestinal and systemic inflammation in genetically susceptible hosts and to identify mechanisms by which normal hosts downregulate bacterial-specific immune responses. The hypothesis is that chronic intestinal and systemic inflammation is the result of an inappropriately aggressive cellular immune response to ubiquitous luminal bacteria, opportunistic pathogens and bacterial products, mediated by a genetically-determined defective downregulation of inflammation. The PI will address several fundamental questions of IBD pathogenesis in the following specific aims: 1) Which components of ubiquitous luminal bacteria induce and perpetuate intestinal inflammation in widely disparate colitis models? 2) Are cellular immune responses to luminal bacterial constituents intrinsically different in genetically susceptible versus resistant hosts? These studies will be performed by experienced investigators with diverse backgrounds who will each bring defined areas of expertise in animal models, gnotobiotic research, and mucosal immunology to the project. Successful completion of these specific aims will provide essential insights into the pathogenesis of IBD and suggest novel therapeutic approaches targeting etiologic mechanisms.
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