Mechanisms Of Placental Nutrient Sensing In The Baboon

狒狒胎盘营养感应机制

• 批准号: 8609092
• 负责人: Thomas Jansson
• 金额: $ 16.28万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8609092
• 关键词: Address; Adult; American; Amino Acid Transporter; Amino Acids; Animals; Brain; Cell membrane; Cells; Development; Disease; Down-Regulation; Epigenetic Process; Essential Amino Acids; Fetal Growth; Fetal Growth Retardation; Folate; Food; Genes; Gestational Age; Glucose; Glucose Plasma Concentration; Glucose Transporter; Growth; Hormones; Household; Human; Hunger; Instruction; Insulin; Insulin-Like Growth Factor I; Intake; Kidney; Knowledge; Label; Leptin; Leucine; Life; Link; Measures; Mediator of activation protein; Messenger RNA; Metabolism; Methionine; Methylation; MicroRNAs; Modeling; Molecular; Nutrient; Outcome; Papio; Pattern; Peptides; Placenta; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Proteins; Pregnant Women; Principal Investigator; Protein Biosynthesis; Proteins; Proteomics; Public Health; Relative (related person); Rodent; Role; SLC2A1 gene; Serum; Sheep; Signal Pathway; Signal Transduction; Signaling Protein; Small Nucleolar RNA; Stable Isotope Labeling; Structure; Supplementation; Syncytiotrophoblast; System; Testing; Tissues; Vitamin B 12; Work; adipokines; adiponectin; cytokine; detection of nutrient; experience; fetal; fetal programming; high throughput technology; improved; in vivo; innovation; mTOR protein; maternal nutrient restriction; maternal serum; nonhuman primate; novel; nutrition; pregnant; programs; protein expression; response; sensor; stable isotope; taurine transporter; transcriptomics; treatment strategy; trophoblast

The mechanisms linking matemal nutrient restriction to reduced fetal growth and programming of adult disease remain to be fully established. We have proposed that the placenta functions as a nutrient sensor, regulating placental nutrient transporters, and therefore fetal growth, in response to changes in the ability of the matemal supply line to deliver nutrients to the placenta. We will test the central hypothesis that inhibition of placental insulin/IGF-l, leptin and mTOR signaling constitute a key molecular link between maternal nutrient restriction, reduced fetal growth and fetal programming by downrregulatlon of placental nutrient transporters, which limits fetal supply of amino acids and methyl donors. We will study matemal nutrient restriction (IVINR, -^30% nutrient intake) in pregnant baboons. Placentas from control and MNR baboons will be studied at two gestational ages (GD 140 and 180). In Aim 1, we will determine the effect of MNR on matemal metabolism, placental signaling and protein synthesis. We will measure maternal hormone, adipokine and nutrient levels and placental insulin/IGpTl, leptin, mTOR, AMPK, GCN2, and GSK3 signaling. Synthesiis of specific proteins will be determined by quantitative proteomics using Stable Isotope Labeling with Amino acids in Culture (SILAC), dimethyl labeling and LC-MS/MS. In Aim 2 the impact of MNR on placental transport and fetal serum concentrations of nuti-ients and methyl donors will be established. The activity and protein expression of transporters for glucose, amino acids and methyl donors (folate, vitamin B12) will be determined in syncytiotrophoblast plasma membranes. In vivo transplacental transport of amino acids will be measured using stable isotopes. In both Aim 1 and 2, we will use high throughput discovery approaches (Next Gen sequencing) to discover additional and novel placental signaling pathways and transporters regulated by MNR. In Aim 3 we will determine the role of leucine and placental mTOR signaling in linking MNR to decreased placental nutrient transport and reduced fetal growth. MNR animals will be Supplemented with leucine from GD 30. The activity and expression of placental mTOR signaling and transporters for glucose, amino acids and metiiyl donors, and fetal nutrient levels and growth will be determined. Significance: Matemal under nutrition is a serious public health problem in the US and worldwide. This work will explore the molecular mechanisms linking MNR to altered placental function and reduced fetal growth in the non-human primate. Innovation: The placental nutrient sensing hypothesis is conceptually novel and challenges the traditional view of how placental function is regulated. RELEVANCE (See instructions): Maternal under nutiition during pregnancy remains a daunting problem worldwide and more than 50 million Americans live in households experiencing food insecurity or hunger. We will explore the mechanisms linking matemal nutrient restriction to altered placental function and reduced fetal growth in the non^human primate. It is expected that this knowledge will improve our understanding of the causes underlying common pregnancy complications and may allow the development of novel treatment strategies.

母体营养限制与胎儿生长和成人发育迟缓之间的联系机制 疾病仍有待完全确定。我们提出胎盘具有营养传感器的功能， 调节胎盘营养转运蛋白，从而响应胎儿生长的能力变化 将营养物质输送到胎盘的母体供应线。我们将检验抑制作用的中心假设 胎盘胰岛素/IGF-1、瘦素和 mTOR 信号传导构成了母体之间的关键分子联系 胎盘营养下调导致营养限制、胎儿生长和胎儿编程减少 转运蛋白，限制氨基酸和甲基供体的胎儿供应。我们将研究物质营养素 怀孕狒狒的限制（IVINR，-^30% 营养摄入）。来自对照和 MNR 狒狒的胎盘将 在两个胎龄（GD 140 和 180）进行研究。在目标 1 中，我们将确定 MNR 对 物质代谢、胎盘信号传导和蛋白质合成。我们会测量母体荷尔蒙， 脂肪因子和营养水平以及胎盘胰岛素/IGpT1、瘦素、mTOR、AMPK、GCN2 和 GSK3 信号传导。 特定蛋白质的合成将通过使用稳定同位素标记的定量蛋白质组学来确定 培养物中的氨基酸 (SILAC)、二甲基标记和 LC-MS/MS。在目标 2 中，MNR 对 将确定营养素和甲基供体的胎盘转运和胎儿血清浓度。这 葡萄糖、氨基酸和甲基供体（叶酸、维生素 B12) 将在合体滋养层质膜中测定。体内氨基经胎盘转运 将使用稳定同位素测量酸。在目标 1 和 2 中，我们将使用高吞吐量发现 方法（下一代测序）发现额外的和新颖的胎盘信号传导途径和 受 MNR 监管的转运蛋白。在目标 3 中，我们将确定亮氨酸和胎盘 mTOR 信号传导的作用 将 MNR 与胎盘营养转运减少和胎儿生长减少联系起来。 MNR 动物将 补充 GD 30 的亮氨酸。胎盘 mTOR 信号传导的活性和表达以及 葡萄糖、氨基酸和甲基供体的转运蛋白，以及胎儿的营养水平和生长将受到影响 决定。意义：在美国，母亲营养不良是一个严重的公共卫生问题 全世界。这项工作将探讨 MNR 与胎盘功能改变之间的分子机制，以及 减少非人类灵长类动物的胎儿生长。创新：胎盘营养感应假说是 概念新颖，挑战了胎盘功能如何调节的传统观点。 相关性（参见说明）： 母亲怀孕期间营养不良仍然是全世界面临的一个严峻问题，超过 5000 万人 美国人生活在粮食不安全或饥饿的家庭中。我们将探讨联动机制 母体营养限制会改变非人类灵长类动物的胎盘功能并减少胎儿生长。 预计这些知识将提高我们对常见问题背后原因的理解 妊娠并发症并可能允许开发新的治疗策略。