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).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK033487-09
Application #
2139072
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1987-01-05
Project End
1995-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
9
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Sukumar, N; Mathews, F S; Gordon, M M et al. (2009) Postcrystallization Analysis of the Irreproducibility of the Human Intrinsic Factor-Cobalamin Complex Crystals. Cryst Growth Des 9:348-351
Mathews, F S; Gordon, M M; Chen, Z et al. (2007) Crystal structure of human intrinsic factor: cobalamin complex at 2.6-A resolution. Proc Natl Acad Sci U S A 104:17311-6
Mahmood, Akhtar; Shao, Jian-su; Alpers, David H (2003) Rat enterocytes secrete SLPs containing alkaline phosphatase and cubilin in response to corn oil feeding. Am J Physiol Gastrointest Liver Physiol 285:G433-41
Shao, J; Sartor, R B; Dial, E et al. (2000) Expression of intrinsic factor in rat and murine gastric mucosal cell lineages is modified by inflammation. Am J Pathol 157:1197-205
Wen, J; Kinnear, M B; Richardson, M A et al. (2000) Functional expression in Pichia pastoris of human and rat intrinsic factor. Biochim Biophys Acta 1490:43-53
Brada, N; Gordon, M M; Shao, J S et al. (2000) Production of gastric intrinsic factor, transcobalamin, and haptocorrin in opossum kidney cells. Am J Physiol Renal Physiol 279:F1006-13
Mathur, A; Sims, H F; Gopalakrishnan, D et al. (1999) Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. Circulation 99:1337-43
Zhou, Y; Kelly, D P; Strauss, A W et al. (1999) Characterization of the human very-long-chain acyl-CoA dehydrogenase gene promoter region: a role for activator protein 2. Mol Genet Metab 68:481-7
Syder, A J; Guruge, J L; Li, Q et al. (1999) Helicobacter pylori attaches to NeuAc alpha 2,3Gal beta 1,4 glycoconjugates produced in the stomach of transgenic mice lacking parietal cells. Mol Cell 3:263-74
Li, Q; Karam, S M; Coerver, K A et al. (1998) Stimulation of activin receptor II signaling pathways inhibits differentiation of multiple gastric epithelial lineages. Mol Endocrinol 12:181-92

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