Biomarkers and Genes Associated with Placental Development and Function in Response to Environmental Pollution

与胎盘发育和响应环境污染的功能相关的生物标志物和基因

• 批准号: 9197901
• 负责人: Sherin U Devaskar
• 金额: $ 64.96万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197901
• 关键词: Adult; Air; Air Pollution; Biological; Biological Markers; Birth; Blood; Chronic; Coronary Arteriosclerosis; DNA Methylation; Data; Development; Discipline of obstetrics; Disease; Early Diagnosis; Environmental Exposure; Environmental Pollution; Epidemiology; Exposure to; Fetal Growth Retardation; Fetus; First Pregnancy Trimester; Functional disorder; Future; Genes; Goals; Gold; Grant; High Risk Woman; Histology; Image; Individual; Industry; Interdisciplinary Study; Investigation; Machine Learning; Malignant Neoplasms; Maps; Measures; Methylation; MicroRNAs; Modeling; Molecular Profiling; Mothers; Motor Vehicles; Normalcy; Outcome; Pathology; Placenta; Placenta Diseases; Placental Insufficiency; Placentation; Pollution; Population; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnant Women; Premature Birth; Prevention strategy; Proxy; Recruitment Activity; Rest; Risk; Second Pregnancy Trimester; Socioeconomic Status; Testing; Therapeutic Intervention; Third Pregnancy Trimester; Time; Tissues; Toxic Environmental Substances; Toxin; Training; Validation; adverse pregnancy outcome; base; bisulfite sequencing; cohort; epigenome-wide association studies; exosome; implantation; in vivo; infant morbidity; molecular marker; novel; primary outcome; response; trafficking; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT Many epidemiological investigations have associated exposure to traffic-derived air pollution from motor vehicles, air toxins from industry, and other environmental toxins with measures of poor birth outcomes consisting of preeclampsia (PE), preterm birth (PTB) and intra-uterine growth restriction (IUGR). These conditions, which collectively constitute ischemic placental disease, correlate strongly with infant morbidity and a host of adult diseases, ranging from coronary artery disease to cancer. Although it is widely believed that the pathophysiological mechanisms leading to complications of ischemic placental disease and placental insufficiency have similar biological origins, starting as early as defective placental implantation, to date there are no predictive studies that prospectively examine placental function. Thus, non-invasive assessment and prediction of normalcy versus aberrancy of placental function are lacking. Therefore, the overarching objective of this proposal is to develop and evaluate a suite of exosomal micro-transcriptomic and transcriptomic signatures (predictor) for predicting placental insufficiency. Moreover, we seek to use these novel signatures to assess the impact of environmental pollution exposure on placental aberrancy/insufficiency and related outcomes (PE, PTB and IUGR) (primary outcome). Our central hypothesis is that chronic exposure to environmental pollution, independent of socio-economic status (SES), increases the risk of placental insufficiency due to early gestational development of adverse placental function, and that these outcomes can be predicted non-invasively by developing maternal blood derived placental-enriched exosomal micro-transcriptomic and transcriptomic signatures. To test this hypothesis, our specific aims are to: AIM 1: Develop non-invasively in maternal blood, placenta-derived exosomal micro- transcriptomic and transcriptomic signatures that predict in-vivo placental function through all three trimesters. AIM 2: Use the micro-transcriptomic and transcriptomic data from Aim 1 to predict environmental pollution data collected during the course of this study. We will construct models to predict the environmental pollution state based on these signatures, so that they may be used as proxy of the pollution when this data is not available. AIM 3: Perform Epigenome Wide Association Studies using DNA methylation from placental tissues of the same cohort. We will use our Reduced Representation Bisulfite Sequencing to identify loci whose methylation is associated with placental insufficiency and environmental exposures. These studies will help identify genes confirmed by transcriptomic analysis that may be useful in future development of therapeutic interventions for women at high risk of placental insufficiency due to air pollution exposures. Identification of molecular signatures that predict the presence of environmental pollution and adverse pregnancy outcomes may become a game-changer. Obstetric practices may embrace these surveillance tactics in real-time to predict and perhaps reverse placental aberrancy/insufficiency.

项目概要/摘要 许多流行病学调查都表明暴露于机动车造成的交通空气污染 车辆、工业空气毒素和其他环境毒素以及不良出生结果的衡量标准 包括先兆子痫（PE）、早产（PTB）和宫内生长受限（IUGR）。这些 这些病症共同构成缺血性胎盘疾病，与婴儿发病率密切相关， 一系列成人疾病，从冠状动脉疾病到癌症。尽管人们普遍认为 缺血性胎盘病及胎盘并发症的病理生理机制 功能不全具有相似的生物学起源，早在有缺陷的胎盘着床时就开始，迄今为止存在 没有前瞻性研究胎盘功能的预测性研究。因此，非侵入性评估和 缺乏对胎盘功能正常与异常的预测。因此，总体目标 该提案的目的是开发和评估一套外泌体微转录组和转录组 用于预测胎盘功能不全的特征（预测因子）。此外，我们试图利用这些新颖的签名 评估环境污染暴露对胎盘异常/不足及相关的影响 结果（PE、PTB 和 IUGR）（主要结果）。我们的中心假设是，长期暴露于 与社会经济地位 (SES) 无关的环境污染会增加胎盘损伤的风险 由于胎盘功能不良导致妊娠早期发育不足，并且这些 通过开发富含胎盘的母血，可以无创地预测结果 外泌体微转录组和转录组特征。为了检验这个假设，我们的具体目标 目的是： 目标 1：在母体血液中非侵入性地开发胎盘来源的外泌体微 通过所有三个预测体内胎盘功能的转录组学和转录组学特征 三个月。目标 2：使用目标 1 中的微转录组和转录组数据进行预测 在本研究过程中收集的环境污染数据。我们将构建模型 根据这些特征来预测环境污染状况，从而可以作为环境污染状况的代理。 当无法获得该数据时，污染。目标 3：使用 DNA 进行表观基因组广泛关联研究 来自同一队列的胎盘组织的甲基化。我们将使用我们的还原代表性亚硫酸氢盐 测序以确定其甲基化与胎盘功能不全和环境相关的位点 曝光。这些研究将有助于识别通过转录组分析证实的基因，这些基因可能有助于 针对因空气导致胎盘功能不全的高风险女性的治疗干预措施的未来发展 污染暴露。识别预测环境污染存在的分子特征 不良妊娠结局可能会改变游戏规则。产科实践可能包括这些 实时监测策略来预测并可能逆转胎盘异常/不足。