Development changes in the mouse intestine are similar to many of the changes that are known to occur in the human gut. We propose to use mammalian genetics to study regulation of gene expression in the developing mouse gastrointestinal tract. This proposed study will use well characterized cDNA clones to measure mRNA concentrations during intestinal maturation. These clones encode apolipoproteins AI and AIV, distinct fatty acid binding proteins, 2 cellular retinol binding proteins, and an intestinal protein of unknown function that is induced during the weaning phase of development. The mRNA levels will be measured in genetically diverse inbred strains of normal mice including mice from three different species. In addition, we will analyze mutant mice that have abnormal intestinal and/or liver function affecting lipid metabolism. Once we have determined the chromosomal locations of the structural genes mentioned above and measured the genetic variation in their expression among the different mouse strains, it will be possible to identify and analyze regulatory genes that control intestinal differentiation. In parallel with the genetic studies, we will examine the effect thyroxine and glucocorticoids have on intestinal maturation at the molecular level. The cDNA probes will be used to determine at which times during gastrointestinal development expression of specific genes is regulated by these two hormones. The studies on thyroxine will utilize the hypothyroid mutant mouse, hyt, with and without replacement therapy. The role of glucocorticoids will be determined by injection of cortisone acetate into normal mice at 4 and 8 days of age to see whether precocious changes in levels of gene expression can be elicited. The mammalian intestine is a unique developmental system and regulation of its maturation has profound effects on the overall metabolism of an individual from birth through adult life. Normal growth and survival in a particular environment requires that the intestine develop or adapt to meet the general nutritional requirements of the organism.
The specific aims are designed to define the genetic and hormonal mechanisms that regulate intestinal function. The long-term goal is to eventually understand how transcription of coordinately regulated genes that are expressed at each stage of intestinal development is controlled at the molecular level.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK037960-02
Application #
3237020
Study Section
Molecular Cytology Study Section (CTY)
Project Start
1987-01-05
Project End
1989-12-31
Budget Start
1988-01-01
Budget End
1988-12-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Thai, Tiffany L; Yu, Ling; Eaton, Douglas C et al. (2014) Basolateral P2X?channels stimulate ENaC activity in Xenopus cortical collecting duct A6 cells. Am J Physiol Renal Physiol 307:F806-13
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Wice, B M; Gordon, J I (1998) Forced expression of Id-1 in the adult mouse small intestinal epithelium is associated with development of adenomas. J Biol Chem 273:25310-9
Garabedian, E M; Roberts, L J; McNevin, M S et al. (1997) Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice. J Biol Chem 272:23729-40
Wong, M H; Hermiston, M L; Syder, A J et al. (1996) Forced expression of the tumor suppressor adenomatosis polyposis coli protein induces disordered cell migration in the intestinal epithelium. Proc Natl Acad Sci U S A 93:9588-93
Bry, L; Falk, P G; Midtvedt, T et al. (1996) A model of host-microbial interactions in an open mammalian ecosystem. Science 273:1380-3
Rowe, L B; Sweet, H O; Gordon, J I et al. (1996) The fld mutation maps near to but distinct from the Apob locus on mouse chromosome 12. Mamm Genome 7:555-7
Hermiston, M L; Gordon, J I (1995) In vivo analysis of cadherin function in the mouse intestinal epithelium: essential roles in adhesion, maintenance of differentiation, and regulation of programmed cell death. J Cell Biol 129:489-506

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