Maternal circulating miRNA function in Fetal Alcohol Spectrum Disorders

母体循环 miRNA 在胎儿酒精谱系疾病中的功能

• 批准号: 9468565
• 负责人: Alexander Mike Tseng
• 金额: $ 3.23万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9468565
• 关键词: Address; Affect; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Analysis of Variance; Behavior; Bioinformatics; Biology; Brain; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Child; Clinical; Craniofacial Abnormalities; Development; Diagnosis; Diagnostic; Disease; Ectoderm; Embryo; Embryonic Development; Endocrine; Endoderm; Ephrins; Epithelial; Ethanol; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Development; Fetal alcohol effects; Fetus; Germ Layers; Goals; Growth; Growth and Development function; Human; Human Cell Line; Impairment; Infant; Institutes; Intervention; Mediating; Mesenchymal; Mesoderm; MicroRNAs; Mission; Modality; Modeling; Mothers; Mus; National Institute of Neurological Disorders and Stroke; Neuroectoderm; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Pattern; Physicians; Placenta; Placentation; Plasma; Pregnancy; Pregnant Women; Prevention; Procedures; Reporting; Research; Research Proposals; Research Training; Role; STAT3 gene; School-Age Population; Scientist; Signal Pathway; Teratogens; Testing; Time; Training; Ultrasonography; Work; alcohol effect; alcohol exposure; alcohol related problem; base; circulating microRNA; developmental disease; disability; experience; experimental study; fetal; fetus cell; forest; human female; human male; in utero; in vivo; infant outcome; interest; loss of function; migration; mouse model; neonatal outcome; neurobehavioral; new therapeutic target; non-genetic; novel; offspring; placental morphology; pregnant; prevent; relating to nervous system; repository; stem cell biology; trophoblast; undergraduate research

Project Summary Prenatal alcohol exposure (PAE) is the leading non-genetic cause of intellectual and other brain disabilities. However, fetal alcohol spectrum disorders (FASD), estimated to affect ~2-5% of school-aged children in the US, remain difficult to diagnose and to prevent. Our recent work (PMCID 5102408) identified several circulating microRNAs (miRNAs) in heavy alcohol-consuming pregnant women whose expression levels in the 2nd and 3rd trimester predicted adverse infant outcomes including craniofacial anomalies and neurobehavioral and growth deficits1. Specifically, Analysis of Variance (ANOVA) models identified 11 elevated plasma miRNAs in mothers whose infants were severely affected by alcohol consumption. Using Random Forest Analysis (RFA), we were further able to use a distinct group of miRNAs to classify infants apparently unaffected by ethanol exposure with affected infants as opposed to alcohol unexposed infants. Aside from their diagnostic value, it is unknown if these Maternal circulating miRNAs associated with Adverse Infant Outcomes (M-circmiRNA-aAIO) contribute to the developmental pathologies of FASD. Bioinformatic analysis suggests these circulating miRNAs potentially regulate important hub genes for STAT3 and ephrin signaling pathways, which are in turn known to control cycles of epithelial mesenchymal transition (EMT) crucial for normal embryogenesis and placental and fetal development. Therefore, my overarching hypothesis is that PAE impairs early development by interfering with the endocrine action of circulating maternal miRNAs on both the placenta and fetus. In my research proposal, using both human cell lines and in vivo mouse models, I will test the hypothesis that pathogenic levels of circulating miRNAs mediate effects of ethanol on placenta and fetus and that they control embryo growth and survival by regulating EMT-like behaviors of key placental and fetal cells. The long-term goals of this project will be to develop interventional strategies that exploit the biology of endocrine circulating miRNAs in mitigating negative outcomes due to PAE and other teratogens. My immediate goals will be to define the role of maternal miRNAs, which predict FASD outcomes, on placental and embryo growth and development. Aim 1: Determine the impact of M-circmiRNA-aAIOs on trophoblast growth, survival, migration and invasion under basal and ethanol exposed conditions. Aim 2: Determine the impact of M-circmiRNA-aAIOs on embryonic growth, death, and cellular maturation/differentiation under basal and ethanol exposed conditions. Aim 3: Determine the impact of M-circmiRNA-aAIOs on in vivo fetal development and neonatal outcomes. My studies are expected to uncover novel endocrine and pregnancy related functions of FASD-associated maternal systemic miRNAs and may provide novel therapeutic targets and non-invasive modalities to mitigate effects of PAE. Given its translational potential, this project will further my training as a physician-scientist interested in pursuing both clinical duties and research on early developmental disorders.

项目摘要 产前酒精暴露（PAE）是智力和其他脑残疾的主要非遗传原因。 但是，胎儿酒精谱系（FASD）估计会影响约2-5％的美国学龄儿童 保持难以诊断和预防。我们最近的工作（PMCID 5102408）确定了几个循环 大量饮酒的孕妇中的microRNA（mirnas），她们的表达水平在第二和第三名 孕期预测婴儿的不良后果，包括颅面异常以及神经行为和生长 缺陷1。具体而言，差异分析（ANOVA）模型确定了母亲中11个升高的血浆miRNA 其婴儿受到饮酒的严重影响。使用随机森林分析（RFA），我们是 进一步能够使用不同的miRNA组来将显然不受乙醇暴露影响的婴儿进行分类 与酒精未暴露婴儿相反的受影响的婴儿。除了它们的诊断价值外，是否还不知道 与不良婴儿结果相关的母体循环miRNA（M-Circmirna-Aaio）有助于 FASD的发育病理。生物信息学分析表明，这些循环的miRNA可能有可能 调节STAT3和Ephrin信号通路的重要集线器基因，而这些途径又已知可以控制周期 正常胚胎发生和胎盘的上皮间质转变（EMT）的至关重要的 发展。因此，我的总体假设是，Pae通过干扰了早期发展 循环母体miRNA对胎盘和胎儿的内分泌作用。在我的研究建议中 使用人类细胞系和体内小鼠模型，我将检验以下假设。 循环miRNA介导乙醇对胎盘和胎儿的影响，并控制胚胎生长和 通过调节关键胎盘和胎儿细胞的EMT样行为的生存。该项目的长期目标将 要制定介入的介入策略，以利用内分泌循环miRNA的生物学来缓解 由PAE和其他Teratogen引起的负结果。我的直接目标是定义母性的作用 miRNA，预测FASD结果的miRNA关于胎盘和胚胎的生长和发育。 目标1：确定M-Circmirna-Aaios对滋养细胞生长，生存，迁移和入侵的影响 基底和乙醇暴露条件。 目标2：确定M-Circmirna-Aaios对胚胎生长，死亡和细胞的影响 基础和乙醇暴露条件下的成熟/分化。 目标3：确定M-Circmirna-Aaios对体内胎儿发育和新生儿结局的影响。 我的研究预计将发现与FASD相关的新型内分泌和妊娠相关功能 母体系统性miRNA，可以提供新颖的治疗靶标和非侵入性方式来减轻 PAE的影响。鉴于其翻译潜力，该项目将进一步进一步作为医师科学家的培训 有兴趣从事早期发育障碍的临床职责和研究。