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.

项目摘要/摘要 许多流行病学调查与电动机的交通衍生空气污染有关 车辆，行业的空气毒素和其他环境毒素，其出生结果的度量不佳 由先兆子痫（PE），早产（PTB）和局内生长限制（IUGR）组成。这些 共同构成缺血性胎盘疾病的疾病与婴儿的发病率和 从冠状动脉疾病到癌症的许多成人疾病。尽管人们普遍认为 病理生理机制导致缺血性胎盘疾病和胎盘的并发症 迄今为止 没有前瞻性检查胎盘功能的预测性研究。因此，非侵入性评估和 缺乏对胎盘功能的正常与异常的预测。因此，总体目标 该建议的是开发和评估外泌体微型转录组和转录组的套件 签名（预测指标）用于预测胎盘不足。而且，我们试图使用这些新颖的签名 评估环境污染暴露对胎盘异常/不足和相关的影响 结果（PE，PTB和IUGR）（主要结果）。我们的中心假设是长期暴露于 环境污染，独立于社会经济地位（SES），增加了胎盘的风险 由于不良胎盘功能的早期胎儿发展而导致的不足，并且 可以通过开发富含胎盘富含的母体血液来预测结果 外泌体微观转录组和转录组特征。为了检验这一假设，我们的具体目的 为：目标1：在孕产妇血液，胎盘衍生的外泌体微 - 转录组和转录组特征通过这三个预测体内胎盘功能 三个。 AIM 2：使用AIM 1的微观转录组和转录组数据来预测 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态，以便将其用作代理 当这些数据不可用时污染。 AIM 3：使用DNA进行表观基因组广泛的关联研究 来自同一队列的胎盘组织的甲基化。我们将使用减少的表示bisulfite 测序以识别其甲基化与胎盘功能不全和环境相关的基因座 暴露。这些研究将有助于通过转录组分析确认的基因，这可能在 未来针对因空气引起的胎盘不足风险的女性的治疗干预措施的未来发展 污染暴露。识别预测存在环境污染的分子特征 不良怀孕的结果可能会改变游戏规则。产科实践可能会接受这些 实时监视策略，以预测和可能逆转胎盘异常/不足。