Molecular Antecedents of Miscarriage

流产的分子前因

基本信息

批准号：
10366840
负责人：
RAINA N. FICHOROVA
金额：
$ 76.05万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-19 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366840
关键词：
Address Adverse effects Affect Anatomy Biological Biological Factors Blood Blood Circulation Blood Coagulation Disorders Case-Control Studies Chemical Exposure Chemicals Chromosomal Loss Chromosome abnormality Clinical Communities Conceptions Conceptus Data Data Set Databases Distal Elements Endometrial Enrollment Environmental Exposure Environmental Risk Factor Epigenetic Process Event Functional disorder Gene Expression Gestational Age Glues Health Hemostatic Agents Hormone imbalance Inflammation Injury Laboratories Lead Live Birth Massachusetts Maternal Health Measures Mediating Michigan MicroRNAs Molecular Molecular Profiling National Institute of Child Health and Human Development North America Oxidative Stress Participant Pathway interactions Pattern Phenotype Physiological Placenta Pregnancy Pregnancy Complications Pregnancy loss Pregnant Women Prenatal Diagnosis Process Measure Public Health Public Health Practice Reporting Research Resources Risk Factors Sampling Single Nucleotide Polymorphism Spontaneous abortion Strategic Planning Stress Symptoms Technology Testing Time Tissues Toxic Environmental Substances Translational Repression Untranslated RNA Urine Villous Woman adverse pregnancy outcome base biological specimen archives biomarker-driven circulating microRNA clinical practice cohort diagnostic biomarker differential expression early pregnancy early pregnancy loss environmental chemical health data innovation insight mRNA Transcript Degradation modifiable risk multidimensional data novel predictive modeling prenatal testing prevent prospective public health priorities social social factors sociodemographics socioeconomics stressor toxicant transcriptomics trophoblast

项目摘要

Miscarriage - defined as pregnancy loss prior to 20 weeks of gestation - is the most common pregnancy complication, affecting 10-20% of clinically recognized pregnancies. While advances have been made in noninvasive prenatal diagnosis of chromosomal abnormalities leading to pregnancy loss, the pathophysiology and environmental causes of chromosomally normal losses – the bulk of miscarriages occurring after the 6th gestation week – remain largely unexplained. We hypothesize that microRNAs serve as a physiologic “glue” for common pathways predicting loss of chromosomally normal pregnancies. MicroRNAs are non-coding RNAs that negatively regulate gene expression by inducing translational inhibition or mRNA degradation. Because of their remarkable stability in the circulation and their ability to report on or regulate cellular and tissue phenotypes in distal anatomic sites, they present an attractive novel target for mechanistic and diagnostic biomarker research. miRNA expression is controlled by a variety of exposures not yet deciphered in pregnant women. In our global transcriptomics pilot, we discovered circulating miRNAs that are differentially expressed in typical pregnancy compared to pre-conception and to pregnancy in women who later miscarry. This application responds to a strategic priority identified by NICHD. We leverage the rich dataset of demographic, socio-economic and maternal health data and the biospecimen archive of three large early pregnancy cohorts (>8000 enrolled participants) and align them with technological resources offered under GLP practice by four participating laboratories. Drawing on the largest sample of miscarriages ever examined in relation to prospectively obtained biological data (250 chromosomally normal miscarriages) and building on the technological resources offered under GLP practice by four participating laboratories, we will: Aim 1: Identify prodromal molecular signatures of miscarriage, in pre-miscarriage maternal blood, free of common chromosomal defects: 1.1 identify miRNAs and miRNA-targeted pathways dysregulated in such miscarriages and 1.2 test associations with gestational age at miscarriage;1.3 determine whether hypothesis-driven biomarkers of deficient endometrial function, inflammation, oxidative stress, hormonal imbalance, and coagulopathy/hemostatic injury are associated with such miscarriages; and 1.4. whether they mediate an association between miRNA and miscarriage. Aim 2: Apply omics in maternal urine to identify environmental exposures associated with miscarriages free of common chromosomal defects; and Aim 3: Explore whether miRNA antecedents mediate an association between miscarriage and elements of the maternal exposome, including chemicals, and socioeconomic and health- related stressors. The proposed research will generate high-dimensional data for the research community and open the door to novel predictive models of the adverse effects of chemical exposures in pregnant women. The study is innovative in its focus on understanding mechanisms and environmental exposures associated with miscarriage and may identify molecular predictors and modifiable risk factors of early pregnancy complications.

流产 - 定义为妊娠 20 周之前流产 - 是最常见的妊娠并发症，影响 10-20% 临床认可的妊娠，尽管在这方面已取得进展。导致流产的染色体异常的无创产前诊断、病理生理学染色体正常丢失的环境原因——大部分流产发生在第六胎之后妊娠周——仍然很大程度上无法解释，我们勇敢地认为 microRNA 可以作为生理“粘合剂”。预测染色体正常妊娠失败的常见途径是非编码 RNA。通过诱导翻译抑制或 mRNA 降解来负向调节基因表达。循环中显着的稳定性及其报告或调节细胞和组织表型的能力远端解剖部位，它们为机械和诊断生物标志物研究提供了一个有吸引力的新靶标。 miRNA 表达受多种暴露因素的控制，但在全球孕妇中尚未破译。转录组学试验中，我们发现了在典型妊娠中差异表达的循环 miRNA 与怀孕前和后来流产的妇女的怀孕相比，该应用程序对以下问题做出了反应。我们利用 NICHD 确定的战略重点。三个大型早期妊娠队列的孕产妇健康数据和生物样本档案（> 8000 人登记参与者）并将其与四位参与人员根据 GLP 实践提供的技术资源进行调整实验室利用有史以来最大的流产样本与预期获得的相关。生物数据（250 例染色体正常流产）并以所提供的技术资源为基础根据四个参与实验室的 GLP 实践，我们将：目标 1：识别以下疾病的前驱分子特征：流产，流产前母体血液中，无常见染色体缺陷：1.1 识别 miRNA 和此类流产中 miRNA 靶向途径失调以及 1.2 测试与胎龄的关联流产；1.3 确定假设驱动的子宫内膜功能缺陷、炎症、氧化应激、激素失衡和凝血病/止血损伤与此类相关流产；1.4.它们是否介导 miRNA 与流产之间的关联。母体尿液组学，以确定与流产相关的环境暴露，不含常见的染色体缺陷；以及目标 3：探索 miRNA 前因是否介导两者之间的关联流产和孕产妇暴露的因素，包括化学品，以及社会经济和健康- 拟议的研究将为研究界和相关的压力源生成高维数据。为孕妇化学暴露不良影响的新预测模型打开了大门。该研究的创新之处在于它侧重于理解与相关的机制和环境暴露流产，并可以确定早期妊娠并发症的分子预测因素和可改变的危险因素。