The intestinal epithelium is a complex, continuously renewing monolayer of cells that is adapted for efficient absorption of fluids and nutrients. The differentiated cells lining villi have brush borders with extraluminal enzymes and membrane transporters for digestion and absorption of luminal nutrients. During the newborn period the sources and composition of nutrients are different from those of adults, and the newborn intestinal epithelium is well suited to the high fat, lactose- containing milk diet. With advancing development, the diet and the characteristics of the epithelium change. Lactose is less abundant and sucrose more abundant in the adult dieT. Correspondingly, lactase activity in the brush border of the epithelium decreases near weaning, and sucrase activity is induced. Other biochemical and structural characteristics of the adult intestinal epithelium are also developmentally determined. The timing of intestinal maturation varies with species, but the changes in gene expression and epithelial organization are remarkably common. This proposal uses mice, a species where intestinal development occurs over a relatively short period of time from late gestation until weaning at the end of the third week of life, to examine the mechanisms of intestinal maturation. Glucocorticoid and thyroid hormone levels rise before the beginning of the suckling- weaning transition, and these hormones are able to induce precocious maturation when administered earlier in the suckling period. Consequently, they seem to have a key roles in coordinating intestinal maturation, but their specific actions and the mechanisms of hormone response in the intestinal epithelium are poorly understood. The central hypotheses of this proposal are: 1) glucocorticoid and/or thyroid hormones acting through their specific receptors coordinate both structural and functional developmental events in the intestinal mucosa, 2) these hormones have independent actions on gene transcription and 3) peptide growth factor receptors, important regulators of development and differentiation in other systems, will have a role in glucocorticoid and thyroid hormone response. The long term goal is to determine how structural and functional maturation pathways are established and maintained in the intestinal epithelium.
The specific aims of this proposal are to: 1) characterize the independent actions of glucocorticoid and thyroid hormones on morphological and biochemical patterns of intestinal maturation, 2) determine the cell-specific localization and ontogeny of glucocorticoid receptor and thyroid hormone receptor in the intestine, 3) identify the mechanism of glucocorticoid mediated activation of ileal lipid binding protein gene expression, and 4) correlate peptide growth factor receptor expression during intestinal maturation with glucocorticoid and thyroid hormone responses.
