In this Program Project renewal reapplication, we have continued a narrowed focus to characterize the role of the enterocyte in mucosal barrier function at the interface between microbial luminal stimuli and lymphoid effector response. The enterocyte is the central focus and will be studied with regard to microbial """"""""crosstalk,"""""""" lymphoid-epithelial interactions, inappropriate developmental responses, and as a barrier to microbial penetration. The renewal application consists of five interactive projects supported by two cores, (1) an Administrative Core and (2) a Tissue Culture/Morphology/Xenograph Transplant Core principally in one location in the Mucosal Immunology/Developmental Gastroenterology Laboratories at the Massachusetts General Hospital- East. Project 1 is a new project to study the enterocyte response, in immature human fetal cells, to exo- and endotoxin. Immaturities in signal transduction responses may account for the increased incidence of age- related inflammatory disease and secretory diarrhea in human infants. Project 2 will determine the inflammatory role of mast cell cytokines and leukotrienes in response to bacterial/enterocyte interaction. Project 3 will study the mechanisms of Shigella interaction with the basolateral surface of the enterocyte interaction. Project 3 will study the mechanisms of Shigella interaction with the basolateral surface of the enterocyte at the cellular mechanisms of Shigella interaction with the basolateral surface of the enterocyte interaction. Project 3 will study the mechanisms of Shigella interaction with the basolateral surface of the enterocyte at the cellular/molecular level. Two new projects have been added to the renewal application. Project 4 will define the role of neuropeptides, specifically corticotrophin releasing factor (CRF) in the intestinal inflammatory response to Clastridial toxins and Project 5 will determine the role of tight junctions, particularly claudin cell/molecular biology, microbiology, immunology, and developmental biology will work in collaborative fashion to define microbial/epithelial responses in the context of inflammation and mucosal defenses. These studies should provide a better understanding of the pathogenesis of bacterial gastroenteritis and lead to improved ways of preventing infectious diseases of the gastrointestinal tract.
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