The long term objective of this project is to determine the functional significance of structural specializations of alimentary tract mucosae in health and disease. Three areas of significance to normal intestinal mucosal function and to the mucosal response to injury will be studied. I: M cells overlying mucosal lymphoid follicles provide focal sites of permeability through which antigenic molecules and selected microorganisms can breach the epithelial barrier to initiate immune responses or infection. Molecular probes, immunocytochemical methods and morphometry will be used in in vivo and in vitro systems to determine the role of specific cytoplasmic organelles (including microtubles, microfilaments and acidic compartments) in the uptake by adsorptive endocytosis and by fluid phase endocytosis and transport of macromolecules by rabbit and rat M cells. Whether M cells simply shuttle macromolecules across their cytoplasm by vesicular transport or also sort macromolecules into prelysosomal or lysosomal pathways for processing or degradation will be examined in a quantitative fashion. II: A model of localized lectin-induced injury to rat absorptive cell microvilli which resembles injury to microvilli seen in disease (celiac-sprue, tropical sprue) will be studied to: 1) determine the pathway(s) of glycoconjugates from their sites of assembly in ER and Golgi to their incorporation into microvillus membrane in injured and undamaged absorptive cells, 2) assess the role of microtubules in the vectorial transport of membrane components across the terminal web and other cell regions and 3) define alterations in membrane structure and composition associated with microvillus injury and the restitution process. Morphometric, radioautographic and freeze-fracture methods will be used in concert with biochemical analyses of isolated microvillus membranes. III: Since the basement membrane influences expression of differentiated functions by epithelial cells, characterization of its interaction with the epithelium is directly relevant to mucosal diseases such as celiac-sprue and other non- infectious and infectious enteritides in with differentiation is impaired. Using immunocytochemical probes for basement membrane renewal to determine: 1) whether basement membrane synthesis occurs at selected sites or uniformly along the crypt- villus axis, 2) whether epithelial cells slide along or migrate in concert with the basement membrane to which they are applied and 3) which epithelial and/or mesenchymal cells synthesize basement membrane components.
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