This Program Project renewal application continues to have a narrow focus on the role of the enterocytes in mucosal barrier function at the interface between microbial and enterotoxin-mediated stimuli and immune effector responses. The enterocyte is the central focus and will be studied with regard to microbial """"""""crosstalk"""""""" immune-epithelial cell interactions, neuropeptide receptor expression, inappropriate developmental responses, and a barrier to microbial penetration. This renewal application consists of five interactive projects supported by two cores, (1) and Administrative Core, and (2) a Xenograft and Isograft Transplant Model Core, principally in one location in the Mucosa Immunology/Developmental Gastroenterology Laboratories at the Massachusetts General Hospital-East. Project 1 will examine the mechanisms involved in the participation of corticotropin-releasing hormone family of neuropeptides and their receptors in the development of mucosal inflammation in response to enterotoxins and bacterial pathogens. Project 2 will determine the mechanistic basis for the developmentally regulated expression of IkappaB in the intestine and evaluate the role of IFNgamma in immunologic maturation of the developing intestine. Developmental differences between fetal and mature enterocytes in Toll-like receptor-related responses will also be examined. Project 3 will study the molecular mechanisms underlying S. flexneri-intestinal epithelial interactions at the apical or basolateral membrane domain that lead to acute infectious colitis. Project 4 will determine the role of GEF-H1, a guanine nucleotide exchange factor (GEF) for Rho, on epithelial cell responses to pathogens and examine the mechanism of this response at the tight junctional level. Project 5 is a new project that will define specific cellular and molecular mechanisms involved in the protective and therapeutic effects of the probiotic agent S. boulardii in enteric infections and enterotoxin-mediated diarrhea and intestinal inflammation. Investigators with disciplines in cell/molecular biology, microbiology, intestinal immunity and inflammation, and developmental biology will work in a collaborative fashion to define microbial-enterotoxin/epithelial responses in the context of inflammation and mucosal defenses. These studies will provide a better understanding of the pathogenesis of bacterial Gl infections and enterotoxin mediated intestinal inflammation and lead to new therapeutic strategies in preventing and treating infectious diseases in the Gl tract.
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