Regulation of Protein Synthesis in Neonatal Sepsis

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DESCRIPTION (provided by applicant): The susceptibility of the neonate for nutritional depletion during illness, and its opposed metabolic ability to utilize nutrients efficiently for growth offers a novel paradigm to evaluate nutrient-hormonal interactions during sepsis. Our long-term objectives are to identify the fundamental mechanisms that regulate amino acid use, including the interaction of hormones, nutrients, and development, in inflammatory conditions such as sepsis. In this proposal, we intend to analyze the pathways that regulate amino acid metabolism in septic neonates. In Aim 1, we hypothesize that raising amino acids in endotoxemic neonates enhances muscle protein synthesis rates. Thus, amino acid dose response studies will be performed in endotoxin (LPS) infused 7- and 26-day-old pigs by using hormone-substrate clamp techniques and in vivo measurement of protein synthesis with isotopic tracer methods. In Aim 2, we wish to determine whether amino acids influence muscle protein synthesis in LPS-infused neonates by affecting activation of translation initiation factors involved in the binding of mRNA, but not met-tRNAi, to the 40S ribosomal complex. Consequently, we will measure in muscle eukaryotic initiation factor (elF) 2B activity, the phosphorylation of eIF4E, 4E-BP1, p70S6 kinase and protein kinase B (PKB), the association of eIF4E with eIF4G and 4E-BP1, and the activation of NFkappaB signaling. In Aim 3, we wish to determine whether muscle proteolysis is enhanced by sepsis in neonates and whether the rate of proteolysis can be suppressed by administration of insulin. Therefore, LPS-infused 7- and 26-day-old pigs subjected to hormone-substrate clamps will be examined using a stable isotopic tracer/mass transorgan balance technique to quantify protein degradation in the hindlimb in the presence of different concentrations of insulin. Knowledge of the nutrient-hormone interface during a critical illness and their developmental distinctiveness can help characterize and optimize the medical management towards recovery and reestablishment of adequate growth after infants and children have been acutely ill.