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Grant Abstract

Grant Number: 1R01HD035679-01
PI Name: Peter Reeds
Project Title: Parenteral Nutrition and Mucosal Amino Acid Metabolism

Abstract: DESCRIPTION: The goal is to quantify the roles of enteral amino acids in intestinal mucosal function, and identify the basis of compromised gut function during parenteral nutrition. Recent isotopic evidence suggests that dietary glutamate is the preferred substrate for mucosal glutathione (GSH) and arginine synthesis. The investigators hypothesize 1: Mucosal GSH and arginine synthesis requires enteral precursors. 2: There is a disproportionate decrease in mucosal GSH and arginine synthesis during TPN. 3: Mucosal GSH and arginine synthesis can be increased by giving enteral supplements of glutamate, glycine and cysteine to animals otherwise maintained by TPN. 4: Omission of these amino acids from enteral feeds will lower mucosal GSH and arginine synthesis but maintain mucosal mass at a higher value than that found in TPN-fed animals. These hypotheses will be tested by achieving the following specific aims: 1: Quantify mucosal GSH and arginine synthesis in animals maintained by enteral elemental diets. 2: Quantify mucosal GSH and arginine synthesis in animals maintained by TPN. 3: Determine whether mucosal GSH and arginine synthesis are increased in animals, maintained by TPN, that are given enteral glutamate, glycine and cysteine. 4: Compare mucosal mass, GSH and arginine synthesis in animals receiving enteral diets that are deficient in glutamate, glycine and cysteine. Multiply-catheterized piglets will receive intravenous or intragastric infusions of [U-13C]glutamate, glutamine and glycine, [2H]-cysteine and [15N]-arginine , to measure the whole body fluxes, portal balances and mucosal uptake of the amino acids. Mass isotopomer distribution analysis of mucosal free and GSH-bound glutamate and mucosal and systemic arginine will be used to identify the source of their precursors. The arginine labeling results will be compared with the mucosal activities of the key enzymes in its synthetic pathway. Identifying the role of specific oral amino acids in mucosal biosynthetic pathways associated with host defenses will aid the development of supplements to help support the nutrient needs and metabolic function of patients receiving TPN.


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