Maturation of the intestinal epithelium is critical for the acquisition of digestive and absorptive functions and thus for survival of the young animal. Rodents constitute a convenient model in which to study this aspect of development, because the final phases of intestinal maturation occur in the postnatal period. Important functional changes occurring at this time include acquiring the ability to digest various carbohydrates found in solid food. The terminal steps of such digestion are accomplished by a family of alpha-glucosidases located on the apical membrane of intestinal epithelial cells. Prior studies have shown that glucocorticoid (GC) hormones can advance the maturation of these enzymes. This GC involvement has clinical significance related to the use of these hormones to stimulate intestinal maturation in premature infants. To further the understanding of GC influence on the developing intestine, the long-term goals of this project are to identify both the cellular and molecular targets of GC action. The further goals are to elucidate the regulation of a neglected member of the alpha- glucosidase family, namely trehalase. The significance of this choice lies in current plans to introduce its substrate trehalose as a sweetener in the U.S. food supply.
Four Specific Aims have been proposed as follows: 1) To use mice lacking the GC receptor (GR-/-) and their wild-type littermates (GR+/+) together with the technique of endoderm-mesenchyme dissociation, reassociation and grafting to determine whether it is the epithelium or the underlying mesenchyme (or both) that serves as the cellular target(s) of GC action on the developing intestine. Critical reassociations will be those in which either the endoderm or the mesenchyme is GR-/-. 2) To develop a co-culture system using mesenchymal cells and epithelial cells from suckling rodent jejunum to allow ultimate testing of genes identified as putative mediators of GC action on the developing intestine. 3) To generate transgenic mice with promoter and enhancer fragments of the mouse trehalase gene in order to delineate the DNA element which mediates GC induction in the postnatal intestine. 4) To use the responsive element defined in Specific Aim 3 to identify the GC-elicited proteins that bind to this sequence and to investigate whether these are known DNA-binding proteins. Such a combination of approaches is proposed as the most efficient way to reveal the multiple steps involved in this complex aspect of intestinal development.
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| Agbemafle, Barbara M; Oesterreicher, Thomas J; Shaw, Chad A et al. (2005) Immediate early genes of glucocorticoid action on the developing intestine. Am J Physiol Gastrointest Liver Physiol 288:G897-906 |
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