Maternal mediators of fetal growth restriction linked to prenatal alcohol exposure

项目摘要/摘要 产前酒精暴露(PAE)是胎儿生长受限(FGR)的常见原因， 这是一个已知的大脑残疾的风险因素。我们之前的研究发现细胞外母体 MiRNAs作为PAE和FGR之间的因果联系。这些针对乌克兰孕妇的研究， 导致11个miRNAs(HEamiRNAs)在重酒血浆中升高- 接触过酒精的母亲随后生下了生长受限、受酒精影响的婴儿(HEA)， 但在那些分娩明显未受影响的婴儿(HEUA)的接触过的母亲中则不是这样，或者 未暴露(UE)的母亲。母体HEamiRNAs共同解释了24%-31%的变异 婴儿出生时的身高、体重和头围，以及啮齿动物、非人类灵长类动物和 在人滋养层细胞系中，解释了PAE对胎盘滋养层上皮细胞的抑制- 间充质转化(EMT)和FGR。在这一建议中的研究，检验了一个创新的假设 乌克兰队列中也发现了两种候选细胞因子，以及细胞外miRNAs， 控制胎儿生长以应对PAE，这些可能被操纵以克服FGR。 在目标1中，我们检验了两个PAE敏感细胞因子，C反应蛋白和sFlt1， 控制母体循环和滋养细胞之间的HEamiRNA转移，作为抑制的一种手段 绒毛的生长，导致FGR。目标2是基于初步研究表明3 在子痫前期和FGR中均升高的HEamiRNAs促进了EMT基因的表达 在滋养层细胞中。我们计划测试细胞因子和出生结果亚群的假设- 可以操纵已定义的HEamiRNAs来克服FGR。AIMS 1和2中的研究将使用CELL 培养和小鼠模型，结合超声成像和转录研究，以评估其作用 细胞因子和HEamiRNAs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HEamiRNAs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)， 在圣地亚哥地区招募的孕妇样本中有和没有证据表明 胎盘功能障碍，包括PAE。我们还将调查HEamiRNAs的分布 在脂蛋白颗粒(LPP)和细胞外小泡(EVS)中确定是否怀孕 和/或胎盘功能障碍与HEamiRNAs在细胞外的重新分布有关 隔室，可能影响其内分泌功能和靶组织分布。 拟议的研究由具有互补技能的合格调查人员领导，遇到了重要的 因以下原因引起的妊娠并发症需要以机制为中心的诊断和干预 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.