Maternal mediators of fetal growth restriction linked to prenatal alcohol exposure

项目总结/摘要 产前酒精暴露（PAE）是胎儿生长受限（FGR）的常见原因， 一个已知的导致大脑残疾的危险因素我们以前的研究发现， miRNAs作为PAE和FGR之间的因果联系。这些研究是在乌克兰的孕妇中进行的， 结果发现了11种miRNAs（HEamiRNAs），这些miRNAs在重度酒精中毒的血浆中升高， 随后分娩生长受限、受酒精影响婴儿的接触母亲（HEa）， 但在分娩明显未受影响婴儿（HEua）的暴露母亲中则没有，或 未暴露（UE）的母亲。母体HEamiRNA共同解释了24-31%的变异， 婴儿出生时的身高、体重和头围，以及啮齿类动物、非人灵长类动物， 在人类滋养层细胞系中，解释了PAE抑制胎盘滋养层上皮细胞- 间质转化（EMT）和FGR。在这个建议的研究，测试一个创新的假设 两种候选细胞因子，也在乌克兰队列中鉴定，和细胞外miRNA， 控制胎儿生长响应PAE，这些可以被操纵，以克服FGR。 在目的1中，我们检验了两种PAE敏感性细胞因子，C-反应蛋白和sFlt 1， 控制母体循环和滋养层之间的HEamiRNA转移，作为抑制 绒毛膜绒毛的生长，导致FGR。目标2是基于初步研究，表明3 在先兆子痫和FGR中升高的HEamiRNA促进了EMT基因的表达， 在滋养层中。我们计划检验细胞因子和出生结果的亚组- 可以操纵定义的HEamiRNA以克服FGR。目标1和2中的研究将使用细胞 培养和小鼠模型，超声成像和转录组学研究，以评估作用 细胞因子和HEamiRNA在PAE介导的胎盘和胎儿生长抑制中的作用。在目标3中， 我们将评估HEamiRNA与其他与胎盘缺陷相关的疾病之间的关系， 发育和功能（先兆子痫、早产、自然流产、FGR）， 来自圣地亚哥地区招募的孕妇的样本，有和没有证据表明 胎盘功能障碍，包括PAE。我们还将研究HEamiRNA的分布， 脂蛋白颗粒（LPPs）和细胞外囊泡（EVs），以确定是否怀孕 和/或胎盘功能障碍与HEamiRNA在细胞外基质中的重新分布有关。 隔室，可能影响其内分泌功能和靶组织分布。 由具有互补技能的合格研究人员领导的拟议研究符合一个重要的 需要以机制为中心的诊断和干预妊娠并发症， PAE和其他病因。

Project Summary/Abstract Prenatal Alcohol Exposure (PAE) is a common cause of fetal growth restriction (FGR), which is a known risk factor for brain disability. Our previous studies identified extracellular maternal miRNAs as a causal link between PAE and FGR. These studies in pregnant women in Ukraine, resulted in discovery of 11 miRNAs (HEamiRNAs) that were elevated in plasma of heavy alcohol- exposed mothers who subsequently delivered growth-restricted, alcohol-affected infants (HEa), but not in exposed mothers who delivered infants that were apparently unaffected (HEua), or unexposed (UE) mothers. Maternal HEamiRNAs collectively explained 24-31% of the variance in infant height, weight and head circumference at birth, and in rodents, non-human primates, and in human trophoblast cell lines, explained PAE inhibition of placental trophoblast epithelial- mesenchymal transition (EMT) and FGR. Studies in this proposal, test an innovative hypothesis that two candidate cytokines, also identified in the Ukraine cohort, and extracellular miRNAs, control fetal growth in response to PAE, and that these may be manipulated to overcome FGR. In Aim 1, we test the hypothesis that two PAE-sensitive cytokines, C-reactive protein and sFlt1, control HEamiRNA transfer between maternal circulation and trophoblasts, as a means to inhibit the growth of chorionic villi, leading to FGR. Aim 2 is based on initial studies that showed 3 HEamiRNAs, which were elevated in both preeclampsia and FGR, promoted EMT gene expression in trophoblasts. We plan to test the hypotheses that cytokines, and sub-groups of birth outcome- defined HEamiRNAs may be manipulated to overcome FGR. Studies in Aims 1 and 2 will use cell culture and mouse models, with ultrasound imaging and transcriptomic studies, to assess the role of cytokines and HEamiRNAs in PAE-mediated inhibition of placental and fetal growth. In Aim 3, we will assess associations between HEamiRNAs, and other conditions linked to defects in placental development and function (preeclampsia, pre-term birth, spontaneous abortion, FGR), in samples from pregnant women recruited in the San Diego region with and without evidence of placental dysfunction, including PAE. We will additionally investigate the distribution HEamiRNAs in lipoprotein particles (LPPs) and extracellular vesicles (EVs) to determine whether pregnancy and/or placental dysfunction is associated with re-distribution of HEamiRNAs among extracellular compartments, possibly influencing their endocrine function and target tissue distribution. The proposed studies, led by qualified investigators with complementary skills, meet a significant need for mechanism-centered diagnoses and intervention for pregnancy complications due to PAE and other etiologies.