The goals of this proposal are to permit the applicant to redistribute a significant proportion of administrative and educational commitments in order that he may develop new techniques for mouse pathobiology research. Specifically, with the explosion of advances in genomics and genetic engineering, the applicant proposes to develop assays in rare event analysis in murine tissues that can be applied to the phenotypic evaluation of genetically altered mice as well as to studies related to the molecular pathogenesis of disease. In addition, the applicant has mentored several trainees and junior investigators in the development of their research programs including the use of animal models and would use the resources to extend these efforts further. The applicant has maintained an active research program that has relied heavily on the use of animal models of chronic inflammation in the digestive tract. While much progress has been made using mouse models to define the role of the host response to flora in the pathogenesis of chronic inflammation, it is still unclear how these events lead to tissue damage and the symptoms associated with colitis and gastroduodenal disease. Activated immune and inflammatory cells that are in intimate contact with the epithelium lead to changes in the absorptive, secretory and barrier functions of the epithelium. Barrier function is quite important as the epithelium normally separates potentially noxious stimuli in the lumen from the underlying tissue. Therefore, loss of this function is important in the pathogenesis of peptic ulcers or colitis caused by luminal acid or flora respectively. The general hypothesis is that immune-mediated damage to gastrointestinal epithelial cells is one of the important components of a multi-factorial process that culminates in gastrointestinal disease associated with chronic inflammation. This hypothesis will be examined in the following specific aims:
Aim #1. Define the mechanisms whereby activated T cells induce epithelial cell damage.
Aim #2. Evaluate the role of Fas/FasL interactions in epithelial cell death in chronic inflammation. This program will provide the applicant training in techniques in rare event analysis that will be an integral part of his own research on the pathobiology of gastrointestinal disease in mouse models. The molecular mechanisms controlling the susceptibility of epithelial cells will be defined on the single cell level and set the stage for future studies on the role for T cells in regulating the expression of genes that define the susceptibility of the host to disease.
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