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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要宫内生长受限（IUGR）是胎儿酒精谱系障碍（FASD）的一个显着特征，产前酒精暴露 (PAE) 的结果胎盘是怀孕期间提供酒精的特殊器官。氨基酸（AA）等营养物质对于胎儿的生长尤其重要。由于胎盘 AA 转运和/或 mTOR 信号传导减少而受到限制，胎儿生长受到损害，并且事实上，在许多与 IUGR 相关的妊娠疾病中，胎盘 AA 的供应会减少。这是否会导致 PAE 中的胎儿生长缺陷仍然未知。 IUGR，至少部分是通过减少胎盘对胎儿的 AA 供应来实现的，这是以下因素的结果我进一步提出下调胎盘 mTOR 信号传导、AA 转运和改变 AA 代谢。正如南非 PAE 队列中所见，母体蛋白质摄入不足会加剧这种功能失调的 AA 为了测试这一点，我将给怀孕的小鼠喂食一种蛋白质—— 整个怀孕期间充足（NP）或低蛋白（LP）饮食，并服用酒精或等热量麦芽糖糊精妊娠晚期 (GD14.5 – GD17.5)，在此期间胎盘急剧上调 AA 转运至在GD17.5时，我将全面评估母体、胎盘和胎儿的AA。目标 1 进行全面的代谢组学分析，以表征 PAE 如何降低 AA。 Aim 2 沿母体-胎盘-胎儿轴的供应和代谢命运进行转录组学分析，胎盘中的蛋白质印迹和免疫组织化学检测胎盘下调的假设 AA 转运蛋白和代谢基因导致 PAE 中 AA 水平的改变，Aim 3 进行了西方研究。胎盘印迹以检验 AA 转运和代谢的这些变化伴随着的假设通过抑制胎盘 mTOR 通路，这是 AA 可用性和胎儿生长的主要调节因子。预测进一步的 PAE 会使 LP 饮食下的这些变化恶化。这些研究使用了尖端技术。创建 PAE 如何影响胎盘 AA 供应的全球概况，并提供关于 PAE 如何影响胎盘 AA 供应的新颖机制见解 PAE 和 PAE-LP 有助于 FASD 中的 IUGR 表型，这些发现为未来奠定了基础。检查产后神经和代谢健康、遗传风险因素的调节作用的研究，以及母亲补充 AA 和/或增加母亲蛋白质摄入量以改善的效果 PAE 妊娠的结果。