Coordination of fetal growth by nutrient availability

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，胎儿体重受母亲营养状况的影响，胎儿生长，如巨大儿和胎儿生长受限等极端情况下的明显观察，与葡萄糖和氨基酸等营养物质的可用性有关。我们假设胎儿营养物质的可用性直接或通过胎儿和胎盘生长因子协调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和胎儿生长受限妊娠以及通过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。本提案的具体目的是：(1)比较正常妊娠和生长受限妊娠的子宫和脐血流量、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和胎儿血浆蛋白合成；（2a）测量母体和胎儿循环生长因子（IGF-1和胎盘生长激素，pGH）、它们的结合蛋白和生长因子结合蛋白和受体的滋养细胞表达；（2b）测定葡萄糖、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）测定正常妊娠和生长受限妊娠中GLUT1葡萄糖转运蛋白和ATA1/2和lat1 /2氨基酸转运蛋白的表达和活性；（3b）测定葡萄糖、氨基酸的影响；IGF-1和pGH对组织外植体和滋养层细胞中GLUT1葡萄糖转运蛋白、ATA1/2和lat1 /2氨基酸转运蛋白的表达和活性的影响，以及（3c）确定营养可利用性是否通过营养感应蛋白激酶mTOR（哺乳动物雷帕霉素靶蛋白）调节滋养层细胞中营养转运蛋白的表达。这些研究将使用两个定义明确的组，一组正常妊娠和一组胎儿生长受限（FGR）。这些组不仅根据出生体重，而且根据生长轨迹和脐带血流量来定义，以确保在真正胎儿生长受限的条件下进行测量。这些研究将首次产生有关该病理、血流、胎儿营养可利用性、经胎盘营养通量、生长因子释放和营养转运蛋白表达的综合数据。这些研究将为更复杂的胎儿生长限制病理研究奠定基础，如先兆子痫和糖尿病，并将为探索营养可利用性转化为调节基因表达和蛋白质合成的信号通路提供基础。

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.