The long term goals of this research are to define and characterize the factors regulating the development of the electrolyte transport mechanisms of the small intestinal epithelial cell. Malabsorption of water and electrolytes is a major pathophysiological feature of many viral and parasitic diarrheas. An understanding of the factors controlling the development and differentiation of the enterocyte may lead to advances in therapeutic regimens for the treatment of viral diarrheas.
The specific aims of the proposed project are to define and characterize the effects of corticosteroids, specifically dexamethasone and aldosterone, on the ontogeny of small intestinal epithelial Na absorption and to relate the time course of the development of electrolyte transport mechanisms to the appearance of enzymic and morphological markers of enterocyte maturation. A novel, cultured epithelial cell line, IPEC1, derived from normal porcine small intestine, will bc used as the model for these studies. This cell line has been shown to develop into monolayer cultures with morphology consistent with differentiated intestinal epithelial cells. Electrogenic Na absorption in response to hydrocortisone has indicated that this cell line is responsive to corticosteroids and is capable of vectorial electrolyte transport. Using chambers and microelectrodes will be used to assess the electrolyte transport and changes in the electrophysiological parameters of the cell membrane in response to dexamethasone and aldosterone. Receptor specificity of the corticosteroids will be determined by specific inhibitors and receptor binding studies. The time course of the development of changes in the electrolyte transport will be examined and correlated to the changes in nutrient transport, enzyme markers and cellular ultrastructure which occur as a function of time or corticosteroid exposure. These studies should provide critical information regarding the role of corticosteroids in the regulation of small intestinal Na transport as well as the factors regulating the differentiation of enterocytes.
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