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: 10706480
• 负责人: CHRISTINA CHAMBERS
• 金额: $ 64.76万
• 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/10706480
• 关键词: Affect; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Biological; Birth; Brain; C-reactive protein; Cell Culture Techniques; Cell Line; Cells; Child; Chorionic villi; Circulation; Cytokine Network Pathway; Data; Defect; Developmental Disabilities; Diagnosis; Diagnostic; Drug or chemical Tissue Distribution; Endocrine; Epithelium; 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; Intervention; Invaded; Link; Lipoproteins; Measures; Mediating; Mediator; 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; Qualifying; 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; 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.

项目概要/摘要 产前酒精暴露 (PAE) 是胎儿生长受限 (FGR) 的常见原因， 已知的脑部残疾危险因素。我们之前的研究发现母体细胞外 miRNA 作为 PAE 和 FGR 之间的因果关系。这些针对乌克兰孕妇的研究， 结果发现了 11 个 miRNA (HEamiRNA) 在重度酒精血浆中升高 - 随后产下生长受限、受酒精影响的婴儿（HEa）的暴露母亲， 但对于生下明显未受影响的婴儿的暴露母亲来说则不然（HEua），或 未暴露（UE）的母亲。母体 HEamiRNA 共同解释了 24-31% 的差异 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作用 间质转化（EMT）和 FGR。研究该提案，测试创新假设 乌克兰队列中也发现了两种候选细胞因子和细胞外 miRNA， 控制胎儿生长以应对 PAE，并且可以操纵这些来克服 FGR。 在目标 1 中，我们测试了以下假设：两种 PAE 敏感细胞因子 C 反应蛋白和 sFlt1， 控制母体循环和滋养层之间的 HEamiRNA 转移，作为抑制的一种手段 绒毛膜绒毛的生长，导致 FGR。目标 2 基于初步研究，结果显示 3 HEamiRNA 在先兆子痫和 FGR 中均升高，促进 EMT 基因表达 在滋养层细胞中。我们计划测试细胞因子和出生结果亚组的假设- 可以操纵定义的 HEamiRNA 来克服 FGR。目标 1 和 2 的研究将使用细胞 培养和小鼠模型，通过超声成像和转录组研究来评估其作用 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 与胎盘缺陷相关的其他病症之间的关联 发育和功能（先兆子痫、早产、自然流产、FGR） 从圣地亚哥地区采集的孕妇样本，有或没有证据表明 胎盘功能障碍，包括 PAE。我们将另外研究 HEamiRNA 的分布 脂蛋白颗粒（LPP）和细胞外囊泡（EV）以确定是否怀孕 和/或胎盘功能障碍与 HEamiRNA 在细胞外的重新分布有关 区室，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研究人员领导，满足了重要的要求 由于妊娠并发症，需要以机制为中心的诊断和干预 PAE 和其他病因。