The purpose of this research project is to determine mechanisms responsible for altered glucose uptake, metabolism, and transport by the growth restricted placenta. These studies are important for defining physiological and biochemical mechanisms responsible for placental dysfunction in the IUGR placenta, as placental insufficiency is responsible for most cases of human IUGR. The nature and mechanisms of these functional deficiencies have not been determined, yet they are fundamental to understanding how the placenta directly affects fetal growth and development. First, we will more completely determine and understand the physiological mechanisms responsible for decreased placental glucose transport capacity and metabolism in the IUGR placenta. Second, we will determine whether changes in GLUT 1 and/or 3 expression are responsible for decreased placental glucose uptake, transport capacity, and metabolism in the IUGR placenta. Third, we will determine whether experimental increases in fetal and/or maternal plasma glucose, insulin, or IGF-I concentrations will increase expression of Glut 1 and/or Glut 3 in trophoblast membranes in the IUGR placenta and normalize glucose transport capacity, thus defining whether deficient glucose transport in the IUGR placenta can be improved by maternal or fetal nutrient and hormone treatments. Experimental approaches include: 1) our established, natural model of placental insufficiency and IUGR in pregnant sheep produced by chronic exposure of the pregnant ewe to a hyperthermic environment; 2) our established but unique Fick principle and radioactive and stable isotopic tracer techniques; 3) established and novel cell and molecular techniques to quantify and localize placental glucose transporters in relation to glucose transport and metabolic kinetics in a variety of trophoblast cells; 4) our established acute and chronic intravenous clamps of glucose, insulin, and IGF-I to determine kinetics of placental glucose uptake, metabolism, and transport rates. These are essential studies to conduct, as IUGR, primarily caused by placental insufficiency, is an important national and international health problem affecting the fetus, neonate, child, and adult.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Application #
Study Section
Nutrition Study Section (NTN)
Program Officer
Ilekis, John V
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University of Colorado Denver
Schools of Medicine
United States
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Rozance, Paul J; Limesand, Sean W; Barry, James S et al. (2009) Glucose replacement to euglycemia causes hypoxia, acidosis, and decreased insulin secretion in fetal sheep with intrauterine growth restriction. Pediatr Res 65:72-8
Hay Jr, William W (2008) Strategies for feeding the preterm infant. Neonatology 94:245-54
Rozance, Paul J; Limesand, Sean W; Barry, James S et al. (2008) Chronic late-gestation hypoglycemia upregulates hepatic PEPCK associated with increased PGC1alpha mRNA and phosphorylated CREB in fetal sheep. Am J Physiol Endocrinol Metab 294:E365-70
Rozance, Paul J; Limesand, Sean W; Zerbe, Gary O et al. (2007) Chronic fetal hypoglycemia inhibits the later steps of stimulus-secretion coupling in pancreatic beta-cells. Am J Physiol Endocrinol Metab 292:E1256-64
Hay, W W (2006) Early postnatal nutritional requirements of the very preterm infant based on a presentation at the NICHD-AAP workshop on research in neonatology. J Perinatol 26 Suppl 2:S13-8
Regnault, Timothy R H; Hay Jr, William W (2006) In vivo techniques for studying fetoplacental nutrient uptake, metabolism, and transport. Methods Mol Med 122:207-24
Rozance, Paul J; Hay, William W (2006) Hypoglycemia in newborn infants: Features associated with adverse outcomes. Biol Neonate 90:74-86
Rozance, Paul J; Limesand, Sean W; Hay Jr, William W (2006) Decreased nutrient-stimulated insulin secretion in chronically hypoglycemic late-gestation fetal sheep is due to an intrinsic islet defect. Am J Physiol Endocrinol Metab 291:E404-11
Hay Jr, William W (2006) Placental-fetal glucose exchange and fetal glucose metabolism. Trans Am Clin Climatol Assoc 117:321-39; discussion 339-40
Hay Jr, William W (2005) Intravenous nutrition of the very preterm neonate. Acta Paediatr Suppl 94:47-56

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