Research undertaken while the candidate completed an NRSA-supported fellowship (T32DK07650) in pediatric nutrition included studies of zinc (Zn) metabolism in young infants with cystic fibrosis. These infants were found to have excessive fecal losses of endogenously secreted Zn. These findings highlighted an important gap in current knowledge of Zn homeostasis. The broad objective of this proposal is to delineate the role of the small intestine in zinc (Zn) homeostasis. Specifically, the processes of absorption of exogenous Zn and secretion and reabsorption of endogenous Zn will be intensively investigated in complex studies in adults. The ability of the human to maintain Zn homeostasis over a very wide range of dietary Zn intake is well documented. Understanding is redimentary, however, of the limits of adaption and how adaptive mechanisms may be affected by other dietary constituents, such as phytate, and disease states, especially those associated with malabsorption. The proposal combines multi-lumen intestinal perfusion techniques with Zn stable isotope methodology and model based compartmental analysis to quantitate and localize the processes of absorption of exogenous Zn and secretion and reabsorption of endogenous Zn. The intestinal perfusion studies allow frequent sampling of intestinal contents from the stomach to the distal ileum during the post-prandial state. Administration of an intravenous Zn isotope prior to the studies will allow measurement of endogenously secretion Zn by isotope dilution. Two additional stable Zn isotopes will be given orally and intravenously at the time of the intestinal studies. Compartmental modeling will be used to integrate direct observations from the gastrointestinal tract with measurements relevant to whole body Zn metabolism to determine rates of absorption and endogenous secretion and reabsorption. Studies will be undertaken during steady state (0-10 days) and nonsteady state (0-8hr) conditions; observations will be obtained form 6 sampling sites in the intestinal lumen, 4 additional tissues and with 3 tracers. Variations of experimental conditions will include a Zn restricted diet; a high phytate to Zn molar ratio; and malabsorption associated with pancreatic insufficiency in CF and the effect of pancreatic enzyme replacement. The candidate will benefit from 2 new senior mentors who will provide the essential training for the intubation/perfusion technique and the model based compartmental analysis. The Colorado CNRU, the University of Colorado Center for human Nutrition and the Pediatric Nutrition laboratories will provide an excellent environment to foster the candidate's development as an independent investigator.
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