Molecular Antecedents of Miscarriage

流产的分子前因

• 批准号: 10686808
• 负责人: RAINA N. FICHOROVA
• 金额: $ 74.09万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 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/10686808
• 关键词: Address; Adverse effects; Affect; Anatomy; Biological; Biological Factors; Blood; Blood Coagulation Disorders; Case/Control Studies; Chemical Exposure; Chemicals; Chromosomal Loss; Chromosome abnormality; Circulation; Clinical; Communities; Conceptions; Conceptus; Data; Data Set; Databases; Distal; Elements; Endometrial; 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; Predisposition; Pregnancy; Pregnancy Complications; Pregnancy loss; Pregnant Women; Prenatal Diagnosis; Process Measure; Public Health; Public Health Practice; RNA; Reporting; Research; Resources; Risk Factors; Risk Marker; 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; biological specimen archives; biomarker driven; circulating microRNA; clinical practice; cohort; comparison control; diagnostic biomarker; differential expression; early pregnancy; early pregnancy loss; environmental chemical; health data; innovation; insight; mRNA Transcript Degradation; modifiable risk; multidimensional data; novel; participant enrollment; predictive modeling; prenatal testing; prevent; prospective; public health priorities; social; social factors; sociodemographics; socioeconomics; stressor; toxicant; transcriptomics; trophoblast

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周之前的妊娠丢失-是最常见的妊娠 并发症，影响10-20%的临床公认的怀孕。虽然已经取得了进展， 非侵入性产前诊断染色体异常导致妊娠丢失，病理生理 以及染色体正常丢失的环境原因--大部分流产发生在第6天之后， 妊娠周-仍然在很大程度上无法解释。我们假设microRNA作为一种生理“胶水”， 预测染色体正常妊娠丢失的常见途径。MicroRNA是一种非编码RNA， 通过诱导翻译抑制或mRNA降解来负调节基因表达。因为他们的 在循环中的显著稳定性以及它们报告或调节细胞和组织表型的能力， 远端解剖部位，他们提出了一个有吸引力的新目标的机制和诊断生物标志物的研究。 miRNA的表达受到各种暴露的控制，这些暴露在孕妇中尚未被破译。在我们的全球 转录组学试验，我们发现循环中的miRNA在典型的妊娠中差异表达， 与怀孕前和怀孕后流产的妇女相比。此应用程序响应一个 国家排雷中心确定的战略优先事项。我们利用丰富的人口、社会经济和 三个大型早孕队列（>8000人登记）的孕产妇健康数据和生物标本档案 参与者），并将其与四个参与者在GLP实践下提供的技术资源保持一致 laboratories.利用有史以来最大的流产样本， 生物学数据（250例染色体正常流产）和所提供的技术资源 根据四个参与实验室的GLP实践，我们将：目标1：确定 流产，在流产前母体血液中，没有常见的染色体缺陷：1.1鉴定miRNA和 miRNA靶向通路在此类流产中失调，1.2试验与孕龄相关， 1.3确定子宫内膜功能缺陷，炎症， 氧化应激、激素失衡和凝血病/止血损伤与这些疾病相关。 流产;和1.4.它们是否介导了miRNA和流产之间的关联。目标2：应用 母亲尿液中的组学，以确定与流产相关的环境暴露， 目的3：探索miRNA前体是否介导了染色体缺陷与 流产和产妇麻烦的因素，包括化学品，以及社会经济和健康- 相关的压力。拟议的研究将为研究界产生高维数据， 打开了一扇大门，以新的预测模型的化学品暴露的不利影响，在孕妇。的 这项研究是创新的，重点是了解机制和环境暴露与 流产，并可能确定分子预测因子和可改变的风险因素的早孕并发症。