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: 10402658
• 负责人: Sze Ting Kwan
• 金额: $ 2.29万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402658
• 关键词: Address; Affect; Alcohol consumption; Alcohols; Amino Acid Transporter; Amino Acids; Award; Behavioral; Biological Process; Blood Circulation; Brain; Branched-Chain Amino Acids; COVID-19 pandemic; Catabolism; Child; Child Health; Chronic Disease; Clinical Research; Cognitive; Communities; Complex; Complication; Consumption; Data Set; Defect; Development; Diet; Dietary Intervention; Dietary Proteins; Down-Regulation; Effectiveness; Essential Amino Acids; Exhibits; Exposure to; FRAP1 gene; Fees; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal Macrosomia; Fetal alcohol effects; Fetus; Functional disorder; Funding; Future; Genes; Health; Health Policy; Immunohistochemistry; Impaired cognition; Impairment; Individual; Institution; Intervention; Low Birth Weight Infant; Manuscripts; Mediating; Medical; Metabolic; Metabolism; Modernization; Mothers; Neurotransmitters; Nutrient; Outcome; Pathway interactions; Phosphorylation; Placenta; Population; Portraits; Pregnancy; Process; Production; Proteins; Public Health; Publishing; Regulatory Pathway; Reporting; Research; Schools; Signal Pathway; Signal Transduction; Study models; Supplementation; Techniques; Technology; Testing; Time; Tissue Harvesting; Western Blotting; after-school program; alcohol effect; alcohol exposure; amino acid metabolism; evidence base; experimental study; fetal; functional status; genetic risk factor; improved outcome; insight; mRNA sequencing; maternal alcohol use; metabolomics; mother nutrition; mouse model; neurobehavioral; novel; offspring; pandemic disease; postnatal; predictive marker; protein intake; relating to nervous system; research study; transcriptomics; uptake

Project Summary/Abstract The purpose for this supplement is to request a funded, 4-month extension for my current F32 award, from August 1st, 2021 to December 31st, 2021. Due to the COVID-19 pandemic, I was unable to continue performing experiments described in Aim 2 of my F32 project because the project under my current F32 award was not designated by my institution as essential research. Furthermore, I am a single mother with a young child, and the pandemic led to the shutdown of my child’s school and many afterschool programs in the local community. Without access to childcare, I had to spend a large amount of time homeschooling my child, which created an additional childcare responsibility and tremendous hardships that significantly hindered my research progress. The requested extension will compensate for the research time loss due to the pandemic, from March 2020 to July 2020. During this 4-month extension, I will complete the immunohistochemical experiments which investigate the cellular distribution of the amino acid (AA) transporters in the alcohol-exposed placentas, as described in Aim 2; these experiments would wrap up a manuscript. I will also finish analyzing the transcriptomic dataset generated from these alcohol-exposed placentas, another experiment described in Aim 2, for a second manuscript that is near-completion. The requested funds will cover my stipends during this 4- month extension period, research supplies needed to complete the immunohistochemistry, and fees for publishing the manuscripts reporting these results. The overall project hypothesis remains unchanged, which states that prenatal alcohol exposure (PAE) causes intrauterine growth restriction, 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. The three specific aims also remain unchanged. 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 the 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 the 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. 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 contributes to intrauterine growth restriction. The request extension will allow me to finish the proposed F32 research studies, which lay groundwork for future research that examines postnatal neural and metabolic health, the modulatory effect of genetic risk factors, and the effectiveness of maternal AA supplementation to improve outcomes of PAE pregnancies.

项目概要/摘要 此补充的目的是请求将我当前的 F32 奖励延长 4 个月，从 2021年8月1日至2021年12月31日。由于COVID-19大流行，我无法继续 执行我的 F32 项目的目标 2 中描述的实验，因为该项目属于我当前的 F32 奖项 没有被我的机构指定为必要研究。此外，我是一位单身母亲，有一个年幼的孩子 孩子，大流行导致我孩子的学校和当地的许多课后项目关闭 社区。由于无法获得托儿服务，我不得不花费大量时间在家教育我的孩子，这 造成了额外的育儿责任和巨大的​​困难，严重阻碍了我的研究 进步。请求的延期将补偿因大流行而造成的研究时间损失，从 2020年3月到2020年7月。在这4个月的延期期间，我将完成免疫组化实验 研究酒精暴露胎盘中氨基酸（AA）转运蛋白的细胞分布， 如目标 2 中所述；这些实验将完成一份手稿。我也将分析完 从这些暴露于酒精的胎盘生成的转录组数据集，Aim 中描述的另一个实验 2，第二份手稿即将完成。所请求的资金将用于支付我这 4 年间的津贴 一个月的延长期、完成免疫组织化学所需的研究用品以及费用 发表报告这些结果的手稿。总体项目假设不变， 指出产前酒精暴露（PAE）会导致宫内生长受限，至少部分是通过减少 胎盘 AA 向胎儿供应，这是胎盘 mTOR 信号下调的结果， AA 运输和改变 AA 代谢。这三个具体目标也保持不变。目标 1 执行 全面的代谢组学分析，用于描述 PAE 如何降低 AA 供应和代谢命运 沿着母体-胎盘-胎儿轴。目标 2 执行转录组学分析、蛋白质印迹和 胎盘免疫组织化学测试胎盘 AA 转运蛋白下调的假设 代谢基因导致 PAE 中 AA 水平的改变。目标 3 在 胎盘来检验 AA 转运和代谢的这些变化伴随着的假设 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。这些 研究使用尖端技术创建 PAE 如何影响胎盘 AA 供应和的全球概况 提供了关于 PAE 如何导致宫内生长受限的新机制见解。请求 延期将使我能够完成拟议的 F32 研究，为未来的研究奠定基础 检查产后神经和代谢健康、遗传风险因素的调节作用以及 母亲补充 AA 改善 PAE 妊娠结局的有效性。