Coordination of fetal growth by nutrient availability

通过营养供应协调胎儿生长

• 批准号: 6905607
• 负责人: Nicholas Illsley
• 金额: $ 37.34万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6905607
• 关键词: aminoacid metabolism; aminoacid transport; binding proteins; clinical research; cord blood; embryogenesis; gene expression; glucose metabolism; glucose transporter; growth factor receptors; hormone metabolism; human pregnant subject; insulinlike growth factor; mother /embryo /fetus nutrition; nutrition related tag; nutritional epidemiology; placenta disorders; placental transfer; pregnancy circulation; prenatal growth disorder; protein biosynthesis; somatotropin; trophoblast; uterus; women' s health; young adult human (21-34)

DESCRIPTION (provided by applicant): There is substantial evidence to show that fetal weight is closely associated with placental weight, that fetal weight is affected by maternal nutritional status and that fetal growth, as observed clearly in extremes such as macrosomia and fetal growth restriction, is related to availability of nutrients such as glucose and the amino acids. We hypothesize that fetal nutrient availability coordinates fetoplacental growth with the expression and activity of placental nutrient transporters either directly, or via fetal and placental growth factors. The proposed studies will examine this hypothesis by comparison of normal and fetal growth restricted pregnancies and by in vitro investigation of the mechanisms involved in regulation of growth factor release and transporter expression. The specific aims of this proposal are (1) to compare uterine and umbilical blood flows, transplacental glucose and amino acid transfer, fetal plasma glucose and amino acid concentrations and fetal plasma protein synthesis in normal and growth restricted pregnancies, (2a) to measure maternal and fetal circulating growth factors (IGF-1 and placental growth hormone, pGH), their binding proteins and trophoblast expression of growth factor binding proteins and receptors, (2b) to determine the effect of glucose, amino acids and IGF-1 on the release of pGH in placental tissue explants and trophoblast cells, (3a) to measure the expression and activity of the GLUT1 glucose transporter and the ATA1/2 and LAT-1/2 amino acid transporters in normal and growth restricted pregnancies, (3b) to measure the effects of glucose, amino acids, IGF-1 and pGH on the expression and activity of the GLUT1 glucose transporter and the ATA1/2 and LAT-1/2 amino acid transporters in tissue explants and trophoblast cells and (3c) to determine whether nutrient availability modulates nutrient transporter expression in trophoblast cells via the nutrient-sensing protein kinase, mTOR (mammalian target of rapamycin). These studies will use two well-defined groups, a group of normal pregnancies and a group suffering from fetal growth restriction (FGR). These groups will be defined not only by birthweight, but also by growth trajectory and by umbilical blood flow, ensuring that measurements are performed in conditions of true fetal growth restriction. These studies will, for the first time, generate integrated data on this pathology, data concerning blood flow, fetal nutrient availability, transplacental nutrient flux, growth factor release and nutrient transporter expression. These studies will lay the foundation for the more complex investigations of fetal growth restriction in pathologies such as preeclampsia and diabetes and will provide the basis for exploration of the signaling pathways by which nutrient availability is converted to signals which regulate gene expression and protein synthesis.

描述（由申请人提供）：有大量证据表明，胎儿体重与胎盘体重密切相关，胎儿体重受母性营养状况的影响，并且胎儿生长（如诸如巨糖症和胎儿生长限制的极端情况下，胎儿的生长）与诸如糖糖和氨基酸等营养的可用性有关。我们假设胎儿​​养分的可用性会与胎盘养分转运蛋白的表达和活性直接或通过胎儿和胎盘生长因子的表达和活性进行协调。拟议的研究将通过比较正常和胎儿生长受限怀孕的妊娠以及对调节生长因子释放和转运蛋白表达涉及的机制进行比较来研究这一假设。 The specific aims of this proposal are (1) to compare uterine and umbilical blood flows, transplacental glucose and amino acid transfer, fetal plasma glucose and amino acid concentrations and fetal plasma protein synthesis in normal and growth restricted pregnancies, (2a) to measure maternal and fetal circulating growth factors (IGF-1 and placental growth hormone, pGH), their binding proteins and trophoblast expression of growth factor binding proteins and receptors, (2b) to determine the effect of glucose, amino acids and IGF-1 on the release of pGH in placental tissue explants and trophoblast cells, (3a) to measure the expression and activity of the GLUT1 glucose transporter and the ATA1/2 and LAT-1/2 amino acid transporters in normal and growth restricted pregnancies, (3b) to measure the effects葡萄糖，氨基酸，IGF-1和PGH的glut1葡萄糖转运蛋白的表达和活性以及组织外植体和滋养细胞细胞中的ATA1/2和LAT-1/2氨基酸转运蛋白以及（3C），以及（3C），以确定营养素是否通过营养不良的细菌蛋白酶蛋白酶蛋白酶蛋白酶蛋白酶蛋白酶蛋白酶在滋养剂中调节营养的转运蛋白，以雷帕霉素）。这些研究将使用两个定义明确的组，一组正常的妊娠和胎儿生长限制（FGR）的组。这些组将不仅通过出生体重来定义，而且还通过生长轨迹和脐带流动来定义，以确保在真正的胎儿生长限制条件下进行测量。这些研究将首次生成有关该病理学的综合数据，有关血流，胎儿养分可用性，移植营养通量，生长因子释放和养分转运蛋白的表达的数据。这些研究将奠定对诸如先兆子痫和糖尿病等病理中胎儿生长限制的更复杂研究的基础，并将为探索信号通路的探索提供基础，这些信号传导途径通过这些信号转化为调节基因表达和蛋白质合成的信号。