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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR051563-03
Application #
7230560
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Boyce, Amanda T
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
3
Fiscal Year
2007
Total Cost
$122,850
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Manjarín, Rodrigo; Suryawan, Agus; Koo, Sue J et al. (2016) Insulin modulates energy and substrate sensing and protein catabolism induced by chronic peritonitis in skeletal muscle of neonatal pigs. Pediatr Res 80:744-752
Hernandez-García, Adriana; Manjarín, Rodrigo; Suryawan, Agus et al. (2016) Amino acids, independent of insulin, attenuate skeletal muscle autophagy in neonatal pigs during endotoxemia. Pediatr Res 80:448-51
Suryawan, Agus; Torrazza, Roberto Murgas; Gazzaneo, Maria C et al. (2012) Enteral leucine supplementation increases protein synthesis in skeletal and cardiac muscles and visceral tissues of neonatal pigs through mTORC1-dependent pathways. Pediatr Res 71:324-31
Wilson, Fiona A; Suryawan, Agus; Orellana, Renan A et al. (2011) Differential effects of long-term leucine infusion on tissue protein synthesis in neonatal pigs. Amino Acids 40:157-65
Gazzaneo, María C; Orellana, Renán A; Suryawan, Agus et al. (2011) Differential regulation of protein synthesis and mTOR signaling in skeletal muscle and visceral tissues of neonatal pigs after a meal. Pediatr Res 70:253-60
Orellana, Renán A; Wilson, Fiona A; Gazzaneo, María C et al. (2011) Sepsis and development impede muscle protein synthesis in neonatal pigs by different ribosomal mechanisms. Pediatr Res 69:473-8
Murgas Torrazza, Roberto; Suryawan, Agus; Gazzaneo, Maria C et al. (2010) Leucine supplementation of a low-protein meal increases skeletal muscle and visceral tissue protein synthesis in neonatal pigs by stimulating mTOR-dependent translation initiation. J Nutr 140:2145-52
Wilson, Fiona A; Suryawan, Agus; Gazzaneo, Maria C et al. (2010) Stimulation of muscle protein synthesis by prolonged parenteral infusion of leucine is dependent on amino acid availability in neonatal pigs. J Nutr 140:264-70
Wilson, Fiona A; Suryawan, Agus; Orellana, Renan A et al. (2009) Feeding rapidly stimulates protein synthesis in skeletal muscle of neonatal pigs by enhancing translation initiation. J Nutr 139:1873-80
Davis, T A; Suryawan, A; Orellana, R A et al. (2008) Postnatal ontogeny of skeletal muscle protein synthesis in pigs. J Anim Sci 86:E13-8

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