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HISTORICAL DESCRIPTIONTranscriptional Regulation of Intestine-Specific Gene Expression during Gut Development and Maturation.The mammalian gastrointestinal tract matures from a primitive tube into morphologically and functionally distinct regions during development. The mature small intestine functions in the digestion and absorption of ingested nutrients. Expression of several nutrient hydrolases is spatially restricted to distinct segments along the cephalo-caudal axis of the small intestine and is temporally regulated during postnatal maturation. Intestinal lactase, the hydrolase responsible for the digestion of lactose in milk, is expressed at highest levels in the jejunal segment of the small intestine shortly after birth and then declines dramatically just prior to weaning in most mammals.Our research is directed towards defining the mechanisms regulating the spatial and temporal restriction of lactase gene expression during intestinal development. The normal maturational decline in lactase enzymatic activity is correlated with a decline in lactase messenger RNA levels and is transcriptionally regulated. We are currently identifying maturation-specific lactase gene cis elements and characterizing the nuclear proteins interacting with those elements in cell culture and transgenic animals. We seek to define the interactions of the lactase gene elements and nuclear factors involved in mediating transcriptional control. The overall goal is to relate these lactase control mechanisms to the broader pathways specifying acquisition of a small intestinal phenotype. We are also investigating gene transfer methods to deliver specific genes to the intestine.