ONTOGENY OF FETAL HEPATIC SERINE AND GLYCINE METABOLISM

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Disorders of fetal growth and development cause significant morbidity and mortality in newborn infants, Growth retardation is present in up to 10% of all newborns admitted to newborn intensive care nurseries and is associated with a poorer neurologic outcome in survivors. Disorders of the metabolism of a variety of amino acids are associated with the development of intrauterine growth retardation or neurologic disease. Thus, amino acid metabolism is a key element that determines the well- being of the human fetus and newborn. We have focused our studies on serine and glycine, two amino acids with unique fetal characteristics. Both amino acids are important precursors for nucleic acid synthesis in the fetus. They have very high turnover rates when compared to other amino acids, implying increased use in the fetus and are poorly transported from the mother to the fetus. The major objective of this grant proposal is to test the hypothesis that in fetal liver, serine and glycine are used predominantly as precursors for nucleic acid synthesis while after birth they are used for gluconeogenesis. This metabolic control is regulated by the combined action of serine hydroxymethyltransferase (SHMT) and the glycine cleavage enzyme system (GCS). The distribution of serine and glycine carbon incorporation into protein, nucleic acids and glycogen its regulation by folate and the effect of growth retardation will be determined in fetal and newborn lamb hepatocytes. The sites of the enzymatic control of fetal hepatic serine and glycine metabolism will be determined using stable isotopes in hepatocytes. The regulation of changes in hepatic SHMT isoenzyme activity will be determined in fetal lamb liver. The role of amino acids and hormones in regulating serine and glycine metabolism, and the activity, protein and RNA expression of their biosynthetic enzymes will be determined in fetal hepatocytes. The mechanism of partitioning of cellular serine and glycine synthesis will be determined. The regulation of placental serine and glycine metabolism will be determined using stable isotopes. This proposed work will determine the ontogeny and metabolic regulation of fetal hepatic serine and glycine metabolism and their metabolic fate. We will determine the cellular mechanism of adaptations in amino acid metabolism that occur at birth. We will determine the relative role of serine and glycine in the perinatal regulation of their metabolism. The understanding of the normal developmental physiology, ontogenic regulation and metabolic adaptation at birth of these amino acids is the first step in understanding their role in normal and abnormal fetal development involving fetal growth and neurologic development.