Coordination of fetal growth by nutrient availability

通过营养供应协调胎儿生长

• 批准号: 7236057
• 负责人: Nicholas Illsley
• 金额: $ 37.47万
• 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/7236057
• 关键词: Affect; Amino Acid Transporter; Amino Acids; Binding Proteins; Blood Circulation; Blood flow; Cells; Clinical; Complex; Condition; Data; Development; Diabetes Mellitus; Diagnostic Procedure; Elements; Endocrine; Ensure; Fetal Growth; Fetal Growth Retardation; Fetal Weight; Fetus; Foundations; Functional disorder; Gene Expression; Genetic; Glucose; Glucose Transporter; Goals; Growth; Growth Factor; Human; Hypoxia; In Vitro; Individual; Insulin-Like Growth Factor I; Investigation; Knowledge; Literature; Low Birth Weight Infant; Malnutrition; Measurement; Measures; Molecular Biology; Mothers; Not Defined; Nutrient; Nutritional status; Output; Pathology; Physiology; Placenta; Placental Growth Factor; Placental Insufficiency; Plasma; Plasma Proteins; Population Study; Pre-Eclampsia; Pregnancy; Protein Biosynthesis; Protein Kinase; Range; Regulation; Research Personnel; Risk; Risk Factors; Role; SLC2A1 gene; Signal Pathway; Signal Transduction; Sirolimus; Small for Gestational Age Infant; System; Techniques; Time; Tissues; Umbilical Blood; Weight; Woman; base; cohort; concept; controlled release; design; detection of nutrient; fetal; fetus nutrition; human HGH-V protein; in vivo; innovation; programs; research study; stem; trophoblast

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，胎儿体重受母亲营养状况的影响，胎儿生长发育，如巨大儿和胎儿生长受限等极端情况下明显观察到的，与可获得的营养物质如葡萄糖和氨基酸有关。我们假设胎儿的营养供应直接或通过胎儿和胎盘生长因子与胎盘营养转运蛋白的表达和活性协调胎儿-胎盘的生长。拟议的研究将通过比较正常和胎儿生长受限的妊娠，以及通过体外研究参与调节生长因子释放和转运蛋白表达的机制来检验这一假说。该建议的具体目的是(1)比较正常妊娠和生长受限孕妇的子宫和脐带血流、经胎盘葡萄糖和氨基酸转移、胎儿血糖和氨基酸浓度以及胎儿血浆蛋白质合成；(2a)检测母婴循环生长因子(IGF-1)和胎盘生长激素(PGH)及其结合蛋白和滋养层细胞生长因子结合蛋白和受体的表达；(2b)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释放PGH的影响。(3a)检测GLUT1葡萄糖转运体和ATA1/2和LAT-1/2氨基酸转运体在正常妊娠和生长受限妊娠中的表达和活性；(3b)检测葡萄糖、氨基酸、IGF-1和PGH对组织外植体和滋养层细胞GLUT1葡萄糖转运体、ATA1/2和LAT-1/2氨基酸转运体表达和活性的影响；(3c)确定营养物质的供应是否通过营养敏感蛋白激酶mTOR(哺乳动物雷帕霉素的靶标)调节滋养层细胞中营养转运体的表达。这些研究将使用两个定义明确的组，一组正常妊娠和一组患有胎儿生长受限(FGR)。这些组将不仅根据出生体重定义，还将根据生长轨迹和脐血流来定义，以确保在真正限制胎儿生长的条件下进行测量。这些研究将第一次产生关于这一病理的综合数据，关于血流、胎儿营养可获得性、经胎盘营养通量、生长因子释放和营养转运体表达的数据。这些研究将为先兆子痫和糖尿病等病理中胎儿生长受限的更复杂的研究奠定基础，并将为探索信号通路提供基础，通过信号通路将营养物质转化为调节基因表达和蛋白质合成的信号。