This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Anaplerotic flux of substrates into and cataplerotic efflux of the tricarboxylic acid (TCA) cycle intermediate via alpha-ketoglutarate and glutamate leads to de novo synthesis of glutamine. Whether these changes in anaplerotic flux are due to changes in protein turnover or by exogenous amino acids has not been examined. It is hypothesized that the administration of a higher amount of exogenous amino acids increases anaplerotic flux of carbon into the TCA cycle, resulting in an enhanced synthesis of glutamine in clinically stable (CS) infants, whereas infants who are acutely ill (AI) will not be able to increase endogenous glutamine synthesis. In the proposed study, premature infants less than 32 weeks with birth weight of less than 1500 gm will be examined between 0-3 days (AI) and 4-10 days (CS) after birth. The response to variable amounts of nitrogen (3 g/kg/d vs 1.5g/kg/d of protein) on glutamine kinetics and leucine N and C kinetics will be examined using [5-15-N] glutamine,[13C15N] leucine tracers as at a prime constant rate infusion. In addition, whole body rate of protein turnover and irreversible oxidation of protein will be quantified using [2H5] phenylaline and [15N2] urea tracers. The concentration of protein in the parenteral nutrition will be either increased (from 1.5g to 3g/kg/d) or reduced (from 3.0 g to 1.5g/kg/d) 19 hours after starting TPN. The concentration of certain important cytokines (TNF alpha, IL-6) that are increased during acute illness and impact protein metabolism will be measured in the plasma. The studies are significant in that they examine: 1) the relationship between the quantity of parenterally administered amino acids and de novo synthesis of glutamine and rate of turnover of proteins; 2) the effect of acute illness on glutamine and protein kinetics; and 3) the relationship between the concentration of inflammatory cytokines and glutamine synthesis and protein turnover. These data will contribute to our understanding of the regulation of glutamine and protein metabolism in premature infants in the immediate newborn period, and may help develop strategies for nutrient intervention in these infants.
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