This Program Project will attempt to characterize the development of intestinal host defenses during the perinatal period and to define pathogenetic mechanisms of infectious and immune-mediated diseases during infancy. Major areas of investigation will include the following: 1) This is a study to characterize developmental differences in the chemical composition of the microvillus membrane surface between immature and mature enterocytes. Our hypothesis is that these developmental differences account for the increased response of newborns to bacterial enterotoxins. Using cholera toxin (CT) and E. coli heat labile toxin (LT) as toxin probes, the presence and characterization of receptors, activation of adenyl cyclase and secretory response will be examined. These studies will help to define defects in the mucosal surface function in immature animals as a component of altered host defenses in newborns. 2) Growth factors and other hormones have been demonstrated to be physiologic components of both rodent and human milk. Some of these peptides may be important for the development of the normal suckling young. Studies of the specific sites of macromolecular uptake and transport in normal and diseased animals at different developmental stages will be undertaken. 3) Since early childhood is a significant period for the development of immune hypersensitivities to environmental antigens, an extensive evaluation to determine what factors in the maternal environment transmitted in utero or via breast milk which may adversely affect the neonate's oral immune responsiveness will be studied. 4) The project will also examine the role of the liver as a second line of mucosal defense with particular emphasis on the development of Kupffer cell functions, i.e., cell surface receptors using monoclonal antibodies, and phagocytosis, as well as the interaction of lymphocytes and hepatocytes in producing acute phase reactants. The major objectives of the Program Project are to characterize intestinal host defense during development in animal models and to define pathogenetic mechanisms of infectious and immune-mediated disease during infancy. Information gained from these studies may be important in understanding intestinal development and disease in infants and children.
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