The overall goal of this program is to examine the function and biology of proteins in gastrointestinal tissues at the cellular and molecular level. Project will study several genes and their protein products expressed in cells of foregut origin (chief and parietal cells of stomach, salivary acini and ducts, pancreatic exocrine cells) (projects 1-3); in enterocytes (projects 4-6), or in hepatocytes (project 6). Gene products to be studied include cobalamin binding proteins (project 1), intrinsic factor (project 2), lipase and colipase (project 3), alpha 1- antitrypsin and antichymotrypsin (project 4), liver and intestinal fatty acid binding proteins (project 5), and long chain acyl CoA dehydrogenase (project 6). Different aspects of the same proteins will be studied in more than one project, reinforcing an integrated approach (intrinsic factor; projects 1, 2; L-FABP, projects 4, 5). Two major focuses are to study the regulation of gene expression in epithelial cells of the gastrointestinal tract, and to determine the relationship between structure and function of certain gastrointestinal proteins. Gene expression will be studied by analysis of transcriptional regulation (projects 2, 3, 4, 6) and in response to environmental factors, such as dietary or hormonal stimuli, during inflammatory response, or adaptation to intestinal reaction or bypass (projects 1, 3, 4, 5, 6). Structure/function studies will include cobalamin binding proteins (project 1), pancreatic lipase and colipase (project 3), and long chain acyl CoA dehydrogenase (project 6). Techniques from molecular biology (projects 1-6), and cell biology (projects 1, 2, 3, 4, 5) will be used. The Program project will utilize the original three core facilities (biomolecular analysis, morphology, and cell culture), including HPLC (for peptide separations), protein sequencers, oligodeoxynucleotide synthesizers, cell culture of intestinal and pancreatic cell lines, light and electron microscopy, computer assisted morphometric analyses, immune localization, and in situ hybridization. These studies will use model systems to provide insights into 1) synthesis and processing of cellular and secreted gastrointestinal proteins, 2) molecular mechanisms of cellular differentiation and adaptation, 3) relationship between structure and function of specific gut proteins, and 4) biochemical changes related to three human disorders, pancreatic insufficiency (project 3), short bowel syndrome (project 5), and long chain acyl CoA dehydrogenase deficiency (project 6).
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