Maternal-fetal amino acid transfer across placenta in a mouse model of prenatal alcohol exposure

产前酒精暴露小鼠模型中母胎氨基酸跨胎盘转移

• 批准号: 9976406
• 负责人: Sze Ting Kwan
• 金额: $ 6.73万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976406
• 关键词: Address; Affect; Alcohol consumption; Alcohols; Amino Acid Transporter; Amino Acids; Behavioral; Biological Process; Blood Circulation; Brain; Branched-Chain Amino Acids; Catabolism; Child; Child Health; Chronic Disease; Clinical Research; Cognitive; Complex; Complication; Consumption; Defect; Development; Diet; Dietary Intervention; Dietary Proteins; Down-Regulation; Effectiveness; Essential Amino Acids; Exhibits; Exposure to; FRAP1 gene; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal Macrosomia; Fetal alcohol effects; Fetus; Functional disorder; Future; Genes; Growth; Health; Health Policy; Immunohistochemistry; Impaired cognition; Impairment; Individual; Intervention; Low Birth Weight Infant; Mediating; Medical; Metabolic; Metabolism; Modernization; Mothers; Mus; Neurotransmitters; Nutrient; Organ; Outcome; Pathway interactions; Phenotype; Phosphorylation; Placenta; Population; Portraits; Pregnancy; Process; Production; Protein-Restricted Diet; Proteins; Public Health; Regulatory Pathway; Reporting; Signal Pathway; Signal Transduction; South African; Study models; Supplementation; Techniques; Technology; Testing; Tissue Harvesting; Western Blotting; alcohol effect; amino acid metabolism; cohort; evidence base; fetal; functional status; genetic risk factor; improved outcome; insight; mRNA sequencing; maltodextrin; metabolomics; mother nutrition; mouse model; neurobehavioral; novel; offspring; postnatal; predictive marker; pregnancy disorder; pregnant; protein intake; relating to nervous system; transcriptomics; uptake

Project Summary/Abstract Intrauterine growth restriction (IUGR) is a distinctive feature of fetal alcohol spectrum disorder (FASD), which is a consequence of prenatal alcohol exposure (PAE). Placenta is a specialized organ of pregnancy that supplies nutrients, such as amino acids (AAs), to the fetus for its growth. AAs are especially important and, when they are limiting due to reductions in placental AA transport and/or mTOR signaling, fetal growth is impaired and IUGR ensues. Indeed, placental AA supply is reduced in many pregnancy disorders associated with IUGR, but whether this contributes to fetal growth deficits in PAE remains unknown. I hypothesize that PAE causes IUGR, at least in part, by reducing placental AA supply to the fetus, and that this is a consequence of downregulated placental mTOR signaling, AA transport, and altered AA metabolism. I further propose that inadequate maternal protein intake, as seen in South African PAE cohorts, worsens this dysfunctional AA metabolism to exacerbate the growth deficits caused by PAE. To test this, I will feed pregnant mice a protein- sufficient (NP) or a low protein (LP) diet throughout pregnancy and administer alcohol or isocaloric maltodextrin during late gestation (GD14.5 – GD17.5), the period during which placenta sharply upregulates AA transport to accelerate fetal growth. At GD17.5, I will comprehensively assess maternal, placental, and fetal AA metabolism. Aim 1 performs a comprehensive metabolomics analysis to characterize how PAE decreases AA supply and metabolic fate along the maternal-placental-fetal axis. Aim 2 performs transcriptomics analysis, western blotting and immunohistochemistry in placenta to test the hypothesis that downregulation of placental AA transporters and metabolic genes contributes to the altered AA levels in PAE. Aim 3 performs western blotting in placenta to test the hypothesis that these changes in AA transport and metabolism are accompanied by inhibition of placental mTOR pathways, which is a major regulator of AA availability and fetal growth. I further predict PAE will exacerbate these changes under a LP diet. These studies use cutting-edge techniques to create a global portrait of how PAE affects placental AA supply and offer novel mechanistic insight into how PAE and PAE-LP contribute to the IUGR phenotype seen in FASD. These findings lay groundwork for future studies that examine postnatal neural and metabolic health, the modulatory effect of genetic risk factors, and the effectiveness of maternal AA supplementation and/or increasing maternal protein intake to improve outcomes of PAE pregnancies.

项目总结/摘要 胎儿宫内生长受限（IUGR）是胎儿酒精谱系障碍（FASD）的一个显著特征， 产前酒精暴露（PAE）。胎盘是一个专门的怀孕器官， 营养素，如氨基酸（AAs），对胎儿的生长。AAs特别重要，当它们 由于胎盘AA转运和/或mTOR信号传导的减少而受到限制，胎儿生长受损， 胎儿宫内发育迟缓事实上，在许多与IUGR相关的妊娠疾病中，胎盘AA供应减少，但 这是否会导致PAE中的胎儿生长缺陷仍不清楚。我假设肺动脉栓塞 IUGR，至少部分，通过减少胎盘AA供应给胎儿，这是一个结果， 下调胎盘mTOR信号传导、AA转运和改变的AA代谢。我进一步提议 在南非的PAE队列中，母亲蛋白质摄入不足， 代谢，以加剧由PAE引起的生长缺陷。为了测试这个，我会给怀孕的老鼠喂一种蛋白质- 在整个妊娠期内给予足够（NP）或低蛋白（LP）饮食，并给予酒精或等热量麦芽糊精 在妊娠晚期（GD14.5 - GD17.5），胎盘急剧上调AA转运至 加速胎儿生长在GD 17.5，我将全面评估母体、胎盘和胎儿AA 新陈代谢.目的1进行全面的代谢组学分析，以表征PAE如何降低AA 供应和代谢命运沿着母-胎盘-胎儿轴。Aim 2进行转录组学分析， Western印迹和免疫组化检测胎盘中的表达，以验证胎盘表达下调的假设。 AA转运蛋白和代谢基因有助于PAE中AA水平的改变。目标3执行西部 在胎盘中进行印迹，以检验AA转运和代谢的这些变化伴随着 通过抑制胎盘mTOR途径，这是AA可用性和胎儿生长的主要调节因子。我 进一步预测，在LP饮食下，PAE将加剧这些变化。这些研究使用尖端技术 创建PAE如何影响胎盘AA供应的全球画像，并提供关于PAE如何影响胎盘AA供应的新机制见解。 PAE和PAE-LP有助于FASD中观察到的IUGR表型。这些发现为未来的研究奠定了基础。 检查产后神经和代谢健康的研究，遗传风险因素的调节作用， 母亲补充AA和/或增加母亲蛋白质摄入量对改善 PAE妊娠的结果。