The objective of the proposed research is to analyze the biological effects of vitamin D metabolites on phosphate and calcium transport in the intestine and kidney. Normal physiological states and two distinct pathophysiological states will be studied. Each is characterized by alterations in vitamin D metabolism, and functional derangements in either calcium and/or phosphate transport. The program is based on the following hypotheses. First, inherited alterations in renal phosphate homeostasis in Familial Hypophosphatemic Rickets (FHR) result from disburbances in renal tubular phosphate transport, and biological responses to vitamin D. Second, acquired derangements in calcium, phosphate, and vitamin D metabolism in the diabetic state result from defective hormonal control of renal cell metabolism and phosphate transport mechanisms. The studies will focus on: (1) the renal metabolism of 25(OH)D3 in a mouse model of FHR, and the relationship of vitamin D metabolites to phosphate transport and protein phosphorylation; (2) the effects of vitamin D metabolites on phosphate transport and phosphorylation of renal cell membranes, (3) the effects of insulin on renal glucose and cyclic nucleotide metabolism and their relationship to brush border membrane protein phosphorylation and phosphate transport; (4) the nature of the defects in renal metabolism of 25-hydroxycholecalciferol in the insulinopenic state: and (5) the relationship of these defects to acquired derangements in intestinal and renal biological response(s) to 1,25-dihydroxycholecalciferol.
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