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.

项目摘要/摘要 介绍性生长限制（IUGR）是胎儿酒精谱系障碍（FASD）的独特特征， 产前酒精暴露（PAE）的结果。 Placeta是供应的专业怀孕器官 胎儿生长的营养素，例如氨基酸（AAS）。 AA尤其重要，当他们 由于放置AA转运和/或MTOR信号传导的减少而受到限制，胎儿生长受到损害，并且 IUGR随之而来。确实，与IUGR相关的许多妊娠疾病中胎盘供应减少了，但是 这是否有助于胎儿生长定义PAE仍然未知。我假设PAE是原因 IUGR，至少部分是通过减少胎儿的占地AA供应，这是 下调胎盘信号传导，AA转运和改变的AA代谢。我进一步提出 如在南非PAE队列中所见，孕产妇蛋白质的摄入量不足，使这种功能失调AA恶化 代谢加剧了PAE引起的生长不足。为了测试这一点，我将喂养怀孕的小鼠蛋白质 - 在整个怀孕期间足够（NP）或低蛋白（LP）饮食，并施用酒精或等型麦芽糊精 在妊娠晚期（GD14.5 - GD17.5）期间，胎盘急剧上调AA的时期 加速胎儿生长。在GD17.5处，我将全面评估Mater，Placenal和胎儿AA 代谢。 AIM 1执行全面的代谢组学分析，以表征PAE如何减少AA 沿着母体 - 易于轴的供应和代谢命运。 AIM 2执行转录组学分析， 植物印迹和免疫组织化学的植物化学，以检验下调节的假设 AA转运蛋白和代谢基因有助于PAE中的AA水平改变。 AIM 3表演西方 plapeta中的印迹以检验以下假设：AA转运和代谢中的这些变化 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剂。我 进一步预测，PAE会在LP饮食下加剧这些变化。这些研究使用尖端技术 为了创建一张全球肖像，说明Pae如何影响PlaceAl AA供应，并提供有关如何如何影响的机械洞察力 PAE和PAE-LP有助于FASD中看到的IUGR表型。这些发现为未来奠定了基础 研究产后神经和代谢健康的研究，遗传危险因素的调节作用以及 母体AA补充和/或增加母体蛋白摄入以改善的有效性 PAE怀孕的结果。