Maternal mediators of fetal growth restriction linked to prenatal alcohol exposure

胎儿生长受限的母体介导因素与产前酒精暴露有关

• 批准号: 10460854
• 负责人: CHRISTINA CHAMBERS
• 金额: $ 66.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460854
• 关键词: Affect; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Biological; Birth; Blood Circulation; Brain; C-reactive protein; Cell Culture Techniques; Cell Line; Cells; Child; Chorionic villi; Cytokine Network Pathway; Data; Defect; Developmental Disabilities; Diagnosis; Diagnostic; Drug or chemical Tissue Distribution; Endocrine; Epithelial; Ethanol; Etiology; Exhibits; Exposure to; Family; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Growth; Fetal Growth Retardation; Functional disorder; Gene Expression; Goals; Growth; Head circumference; Height; Human; Human Cell Line; Infant; Injections; Institutes; Intervention; Link; Lipoproteins; Measures; Mediating; Mediator of activation protein; Mesenchymal; MicroRNAs; Mothers; Mus; Outcome; Outcome Study; Pathology; Pathway interactions; Placenta; Placental Insufficiency; Placentation; Plasma; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnant Women; Premature Birth; Process; Research Personnel; Review Literature; Risk Factors; Rodent; Role; Sampling; School-Age Population; Second Messenger Systems; Second Pregnancy Trimester; Signal Transduction; Spontaneous abortion; Strategic Planning; Subgroup; Testing; Ukraine; Ultrasonography; Vascular Endothelial Growth Factors; Weight; Woman; alcohol consequences; alcohol exposure; alcohol misuse; base; cohort; cytokine; disability; extracellular; extracellular vesicles; fetal; inhibitor; innovation; mimetics; mouse model; nonhuman primate; novel; particle; pregnant; prenatal exposure; prevent; receptor; recruit; response; skills; transcriptomics; translational potential; trophoblast

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.

项目摘要/摘要 产前酒精暴露（PAE）是胎儿生长限制（FGR）的常见原因， 大脑残疾的已知危险因素。我们以前的研究确定了细胞外孕妇 miRNA作为PAE和FGR之间的因果关系。这些研究在乌克兰的孕妇， 导致发现了11个miRNA（heamirnas），这些miRNA（heamirnas）升高在重醇的血浆中 裸露的母亲随后交付了受限制性饮酒的婴儿（HEA）， 但是，没有在暴露的母亲中，这些母亲送给显然不受影响的婴儿（heua）或 未受暴露的（UE）母亲。母亲的Heamirnas共同解释了24-31％的差异 出生时的婴儿身高，体重和头围，啮齿动物，非人类灵长类动物和 在人类滋养细胞细胞系中，解释了PAE抑制胎盘滋养细胞上皮 间充质转变（EMT）和FGR。在该提案中的研究，检验创新的假设 在乌克兰队列中也发现了两个候选细胞因子和细胞外miRNA， 控制胎儿生长对PAE的响应，并且可以操纵这些生长以克服FGR。 在AIM 1中，我们检验了两个对PAE敏感的细胞因子C反应蛋白和SFLT1的假设， 对照heamirna在母体循环和滋养细胞之间的转移，以此作为抑制的一种手段 绒毛膜的增长，导致FGR。 AIM 2基于最初的研究，该研究显示3 在先兆子痫和FGR中均升高的heamirnas促进了EMT基因表达 在滋养细胞中。我们计划测试细胞因子和出生结局的亚组的假设 - 可以操纵定义的Heamirnas以克服FGR。目标1和2中的研究将使用单元格 具有超声成像和转录组研究的培养和小鼠模型，以评估角色 PAE介导的胎盘生长的抑制作用中的细胞因子和HeamiRNA的摄氏。在AIM 3中， 我们将评估Heamirnas与与胎盘缺陷有关的其他条件之间的关联 开发和功能（子痫前期，预期出生，自发流产，FGR）， 来自圣地亚哥地区招募的孕妇的样本，没有证据 胎盘功能障碍，包括PAE。我们还将调查分布heamirnas 在脂蛋白颗粒（LPP）和细胞外囊泡（EV）中，以确定是否怀孕 和/或胎盘功能障碍与细胞外heamirnas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员领导，符合重要的研究 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。