PEDIATRIC IBD--KEY TO EARLY PATHOGENIC EVENTS

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The overall goal of the Program Project is to fill a major gap in current knowledge of IBD pathogenesis by studying children with Crohn's disease and ulcerative colitis, and the progression of early to late stages of disease in animal models of gastrointestinal inflammation. The proposal is the natural outcome of a vigorous and multi-disciplinary expertise in IBD pathophysiology, intestinal immunity, mucosal cytokines, animal model of colitis and gastritis, and immune-non immune cell interaction in intestinal inflammation. The Program Project will investigate will investigate mechanistic links of early to late events of gut inflammation by testing the specific hypotheses proposed in four Research Projects. Project 1: Early IBD in children results from loss of tolerance to antigens of the commensal flora, and its persistence contributes to the chronicity of IBD. Project 2: Inflammation in murine models of IBD is initiated by mucosal T-cell responses to enterobacterial antigens, and it is perpetuated during the late stage of disease by a pro-inflammatory response maintained by mucosal immune and non immune cells. Project 3: Chronic gastrointestinal inflammation results from an aberrant immune response against antigenic stimuli derived from the normal enteric flora, and this response is modulated by immunization and the presence or absence of Helicobacter organisms. Project 4: Specific changes in the composition of the extracellular matrix of mucosal basement membrane contributes crucially to early inflammation, while altered synthesis and modulation of interstitial extracellular matrix foster progression of inflammation from the early to the late stages of disease. These proje3cts will be performed using state-of-the-art methodological strategies including evaluation of tolerance to normal enteric antigens in pediatric and adult IBD patients, immunoregulatory studies in gene-deficient mice with early and late models of intestinal inflammation, colonization by commensal and infectious bacteria in these models, DNA microarray systems for differential gene expression in intestinal inflammation, extracellular matrix gene and protein expression in human and murine models of IBD, and induction of intestinal fibrosis in normal and proteoglycan-deficient mice. The four Projects will be supported by three Service Cores: a Patient Core (A), an Animal Core (B) and an Administrative Core (C).