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.
Showing the most recent 10 out of 35 publications
