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重量密切相关，胎儿体重受母体营养状况和胎儿生长的影响，如在巨大儿和胎儿生长受限等极端情况下清楚观察到的那样，与葡萄糖和氨基酸等营养素的可用性有关。我们假设胎儿​​营养可用性直接或通过胎儿和胎盘生长因子协调胎儿胎盘生长与胎盘营养转运蛋白的表达和活性。拟议的研究将通过比较正常妊娠和胎儿生长受限妊娠以及体外研究涉及生长因子释放和转运蛋白表达调节的机制来检验这一假设。该提案的具体目的是（1）比较正常妊娠和生长受限妊娠中的子宫和脐血流量、经胎盘葡萄糖和氨基酸转移、胎儿血浆葡萄糖和氨基酸浓度以及胎儿血浆蛋白合成，（2a）测量母体和胎儿循环生长因子（IGF-1 和胎盘生长激素，pGH）、其结合蛋白以及生长因子结合蛋白和受体的滋养层表达，(2b) 以确定葡萄糖、氨基酸和IGF-1 对胎盘组织外植体和滋养层细胞中 pGH 释放的影响，(3a) 测量正常和生长受限妊娠中 GLUT1 葡萄糖转运蛋白以及 ATA1/2 和 LAT-1/2 氨基酸转运蛋白的表达和活性, (3b) 测量葡萄糖、氨基酸、IGF-1 和 pGH 对 GLUT1 葡萄糖转运蛋白和 ATA1/2 的表达和活性的影响组织外植体和滋养层细胞中的 LAT-1/2 氨基酸转运蛋白，以及 (3c) 确定营养可用性是否通过营养感应蛋白激酶 mTOR（雷帕霉素的哺乳动物靶标）调节滋养层细胞中的营养转运蛋白表达。这些研究将使用两个明确的组，一组是正常妊娠，一组是患有胎儿生长受限（FGR）的组。这些组不仅根据出生体重来定义，还根据生长轨迹和脐血流量来定义，以确保测量是在真正的胎儿生长受限的条件下进行的。这些研究将首次生成有关该病理学的综合数据、有关血流、胎儿营养可用性、经胎盘营养通量、生长因子释放和营养转运蛋白表达的数据。这些研究将为对先兆子痫和糖尿病等病理学中的胎儿生长受限进行更复杂的研究奠定基础，并将为探索信号通路奠定基础，通过该信号通路将营养物质的有效性转化为调节基因表达和蛋白质合成的信号。