ONTOGENY OF FETAL HEPATIC SERINE AND GLYCINE METABOLISM

胎儿生长和发育障碍导致显著的发病率， 新生儿死亡率，生长迟缓存在于高达10% 新生儿重症监护室收治的所有新生儿中， 与幸存者的神经功能预后较差相关。 障碍 各种氨基酸的代谢与 胎儿宫内发育迟缓或神经系统疾病。 因此，氨基酸代谢是决定良好的关键因素- 人类胎儿和新生儿的存在。 我们的研究集中在 丝氨酸和甘氨酸，这两种氨基酸具有独特的胎儿特征。 这两种氨基酸都是核酸合成的重要前体， 胎儿他们有非常高的周转率时，相比其他 氨基酸，这意味着胎儿使用增加， 从母体转移到胎儿体内 本项目的主要目标是 一项拨款提案是为了验证这样一个假设，即在胎儿肝脏中，丝氨酸和 甘氨酸主要用作核酸合成的前体 而出生后，它们用于生殖。 这种代谢 控制由丝氨酸的联合作用调节， 羟甲基转移酶（SHMT）和甘氨酸裂解酶系统 （GCS）。 丝氨酸和甘氨酸碳掺入的分布 蛋白质，核酸和糖原，其调节叶酸和 将在胎儿和新生羔羊中确定生长迟缓的影响 肝细胞 胎肝丝氨酸的酶促调控部位 和甘氨酸代谢将使用稳定同位素测定， 肝细胞 肝脏SHMT同工酶变化的调控 将在胎羔羊肝脏中测定活性。 氨基酸的作用 和激素调节丝氨酸和甘氨酸代谢， 其生物合成酶的活性、蛋白质和RNA表达将 在胎肝细胞中测定。 分配机制 测定细胞丝氨酸和甘氨酸的合成。 调控 胎盘丝氨酸和甘氨酸代谢将使用 稳定同位素 这项拟议的工作将确定个体发育和 胎肝丝氨酸和甘氨酸代谢的代谢调节， 他们的新陈代谢命运 我们将确定的细胞机制， 在出生时发生的氨基酸代谢的适应。我们将 确定丝氨酸和甘氨酸在围产期的相对作用 调节他们的新陈代谢。 对常态的理解 发育生理学、个体发育调节和代谢适应 在这些氨基酸诞生的第一步是了解他们的 在涉及胎儿生长的正常和异常胎儿发育中的作用， 神经发育

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.