Placenta-derived extracellular circulating RNA as a tool for monitoring placental function

胎盘来源的细胞外循环 RNA 作为监测胎盘功能的工具

• 批准号: 9270567
• 负责人: Zev Williams
• 金额: $ 96.89万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-17 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270567
• 关键词: Automation; Bioinformatics; Biological; Biopsy; Blood; Blood Circulation; Caring; Cells; Clinical; Code; DNA; Detection; Development; Discipline of obstetrics; Disease; Early Diagnosis; Environmental Exposure; Fetus; First Pregnancy Trimester; Functional disorder; Gap Junctions; Gene Expression; Generations; Genes; Genome; Gestational Age; Goals; Health; High-Risk Pregnancy; Hormones; Immune system; Infectious Agent; Laboratories; Libraries; Maps; Maternal Health; Measures; Methods; MicroRNAs; Monitor; Mothers; Neonatal; Organ; Pathogenesis; Physiological; Physiology; Placenta; Plasma; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Premature Birth; Preparation; Procedures; Process; Protocols documentation; RNA; RNA-Binding Proteins; Reproducibility of Results; Research Personnel; Ribonucleases; Risk; Risk stratification; Role; Sampling; Sampling Studies; Second Pregnancy Trimester; Small RNA; Source; Spontaneous abortion; Structure; Syncytiotrophoblast; Technology; Testing; Therapeutic Intervention; Time; Tissues; Toxin; Transcript; Untranslated RNA; Urine; adverse outcome; base; cell type; clinically relevant; cost; cytotrophoblast; extracellular; fetal; healthy pregnancy; improved; in vivo; insight; new technology; non-invasive monitor; novel; nutrition; prevent; public health relevance; screening; single cell sequencing; stillbirth; tool; transcriptome; transcriptome sequencing; wasting

 DESCRIPTION (provided by applicant): The placenta is the nexus between the fetus and mother; placental health is absolutely central and critical to both fetal and maternal health. The placenta is the source of nutrition and oxygenation for the fetus, allows the fetus to eliminate waste, protects it from toxins, environmental exposures, infectious agents and rejection by the maternal immune system, and produces hormones that support the pregnancy. Abnormalities in placental structure and function underlie complications associated with pregnancy, including preterm birth, miscarriage and stillbirth, and hypertensive disorders such as preeclampsia. Therefore, monitoring placental function is necessary in order to prevent adverse outcomes for the mother and the fetus. Early detection of changes in placental function provides the opportunity for increased pregnancy surveillance and treatment. As is the case with every other organ, the functional state of the placenta is reflected by changes in the expression of coding and non-coding genes. Thus, monitoring the transcriptome of the placenta allows for a comprehensive assessment of placental function. The challenge is to be able to assess placental transcriptome without using invasive methods (e.g. placental biopsy) because these methods pose a risk to the pregnancy. To be clinically relevant, this method must be robust, reliable and able to use on large numbers of clinical samples at reasonable costs, and be able to monitor the full placental transcriptome. Unfortunately, these goals are not possible with existing technology. Our laboratory has developed an RNA sequencing method to comprehensively and quantitatively profile extracellular RNA (exRNA), specifically, placental microRNAs (miRNAs), found in maternal circulation. In the proposed project, we will advance this method and develop technology that will enable non-invasive monitoring of the placental transcriptome through the maternal blood and urine. In Aim 1, we will develop two new technologies, automated exRNA Isolation (AxRI) and total short RNA sequencing (tsRNAseq) that will enable isolation and sequencing of coding and non-coding exRNAs from the maternal blood and urine. In Aim 2, we will apply these new technologies to monitor placenta-specific exRNAs in the maternal blood and urine of term and first and second trimester pregnancies; these earlier time points are important because these is the gestational ages when changes in the transcriptome will be the most clinically relevant and biologically informative. In Aim 3, we will define the precise cell-origin of placenta-specific exRNAs to provide contextual information to analysis of the exRNAs. Therefore, the scope of this project provides the unprecedented opportunity to leverage cutting-edge technologies for exRNA isolation and detection, sequencing, and bioinformatics, in order to develop a tool to non-invasively monitor the transcriptome of the placenta in real time. This tool can then be used to gain insights into pathogenesis of pregnancy-related diseases, identify high-risk pregnancies before the onset of end-organ damage and, ultimately, provide therapeutic interventions to improve maternal and neonatal health.

 描述（由申请人提供）：胎盘是胎儿和母亲之间的纽带;胎盘健康对胎儿和母亲的健康至关重要。胎盘是胎儿营养和氧合的来源，允许胎儿排除废物，保护其免受毒素，环境暴露，感染因子和母体免疫系统的排斥，并产生支持妊娠的激素。胎盘结构和功能的异常是妊娠相关并发症的基础，包括早产、流产和死胎，以及高血压疾病如先兆子痫。因此，监测胎盘功能是必要的，以防止对母亲和胎儿的不良后果。早期发现胎盘功能的变化为增加妊娠监测和治疗提供了机会。与其他器官一样，胎盘的功能状态通过编码和非编码基因表达的变化来反映。因此，监测胎盘的转录组可以全面评估胎盘功能。挑战在于能够在不使用侵入性方法（例如胎盘活检）的情况下评估胎盘转录组，因为这些方法对妊娠构成风险。为了具有临床相关性，该方法必须是稳健的、可靠的，并且能够以合理的成本用于大量临床样品，并且能够监测完整的胎盘转录组。不幸的是，这些目标是不可能与现有的技术。我们的实验室已经开发了一种RNA测序方法，可以全面和定量地分析母体循环中发现的细胞外RNA（exRNA），特别是胎盘microRNA（miRNAs）。在拟议的项目中，我们将推进这一方法，并开发技术，使非侵入性监测胎盘转录组通过母体血液和尿液。在目标1中，我们将开发两种新技术，自动exRNA分离（AxRI）和总短RNA测序（tsRNAseq），这将使从母体血液和尿液中分离和测序编码和非编码exRNA成为可能。在目标2中，我们将应用这些新技术来监测足月妊娠和妊娠早期和中期孕妇血液和尿液中的胎盘特异性exRNA;这些早期时间点很重要，因为这些是转录组变化最具临床相关性和生物学信息的孕龄。在目标3中，我们将定义胎盘特异性exRNA的精确细胞来源，以提供exRNA分析的背景信息。因此，该项目的范围提供了前所未有的机会，利用exRNA分离和检测、测序和生物信息学的尖端技术，以开发一种真实的时间非侵入性监测胎盘转录组的工具。然后，该工具可用于深入了解妊娠相关疾病的发病机制，在终末器官损伤发生之前识别高危妊娠，并最终提供治疗干预措施，以改善孕产妇和新生儿健康。