The overall goal of the Program Project is to characterize host- environment interactions within the intestinal tract. Within this central theme, the Program examines the hosts' response to a protein antigen that activates human celiac disease, to an enteric bacterial pathogen, S. dublin, and to the protozoan parasites G. lamblia and E. histolytica. Other aspects of the Program examine the influence of the intestinal environment on S. dublin, G. lamblia and E. histolytica, as well as interactions between key components of the mucosal immune system and those pathogens. The Program consists of six Projects and four Cores, and brings together investigators with substantial expertise in immunology, molecular biology, and microbiology from three Departments and four Divisions to accomplish the Program's major objectives. Research Unit 1, Project 1, will explore the immunogenetic basis of an intestinal disease (celiac disease) that is activated by exposure to common dietary proteins (i.e., wheat gliadins and similar proteins in other grains). Research Unit 1, Project 2, will study the molecular mechanisms by which specific cytokines regulate the late stages of IgA B cell differentiation, will investigate cytokine production by the intestinal epithelium as an early signaling system to the adjacent and underlying cells of the mucosal immune system, and will examine the role mucosal cytokines play in determining host susceptibility and resistance to the enteric pathogen S. dublin. Research Unit 2 will study the hosts' interaction with a protozoan parasite, Giardia lamblia, strategies that the parasite uses to survive in the host and to evade host defense mechanisms and that the host uses in its interaction with this parasite. Research Unit 3 examines virulence plasmid-encoded strategies employed by an enteric pathogen, S. dublin, to avoid both humoral and cellular host defenses and explores factors important for host resistance to Salmonella. Research Unit 4 will examine the molecules on intestinal epithelial cells that are important in the host interaction with gamma/delta T cells, examine the peptides recognized by gamma/delta T cells and in collaboration with Units 2 and 3, characterize the importance of gamma/delta T cells in host defense to bacterial and parasitic pathogens. Facilities in the areas of tissue culture, molecular biology, the development of transgenic lines of mice, murine breeding and maintenance, and administrative services offer quality services and tightly interlink the Projects. This Program has provided significant insights into mechanisms important in intestinal disease and should continue to provide new information and new strategies for the prevention and treatment of intestinal disease.
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