Molecular Antecedents of Miscarriage

流产的分子前因

• 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
• 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; 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

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周之前的怀孕损失 - 是最常见的怀孕 并发症，影响10-20％的临床识别妊娠。虽然已经取得了进步 染色体异常的无创产前诊断导致妊娠丧失，病理生理学 染色体正常损失的环境原因 - 大部分流产发生在第六次之后 妊娠周 - 在很大程度上无法解释。我们假设microRNA是一种生理“胶” 通用途径预测染色体正常妊娠的丧失。 microRNA是非编码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 循环的显着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型目标。 miRNA表达受孕妇尚未决定的各种暴露控制。在我们的全球 转录组试验器，我们发现循环中的miRNA在典型的怀孕中有所不同 与后来失败的妇女的概念和怀孕相比。此申请对 NICHD确定的战略优先级。我们利用人口，社会经济和 孕产妇健康数据和三个大型早期妊娠队列的生物循环档案（> 8000名 参与者），并将他们与GLP实践提供的技术资源保持一致 实验室。利用有史以来获得的最大流产样本 生物学数据（250个染色体正常流产）并在提供的技术资源上建立 在四个参与实验室的GLP实践下，我们将：目标1：确定前驱分子签名 流产，在前马斯卡菌的物物血液中，没有常见的染色体缺陷：1.1识别miRNA和 在此类流产和妊娠年龄的1.2测试关联中，miRNA靶向的途径在 流产； 1.3确定假设驱动的子宫内膜功能，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；和1.4。它们是否介导mirna和流产之间的关联。目标2：申请 孕产妇尿液中的OMICS，以识别与流产有关的环境暴露 染色体缺陷；和目标3：探索miRNA先例是否介导 流产和孕产妇杂物体的要素，包括化学物质以及社会经济和健康 - 相关压力源。拟议的研究将为研究界生成高维数据，并 为孕妇化学暴露的不良反应的新型预测模型打开大门。 研究的重点是理解与与之相关的机制和环境暴露的创新性 流产，并可能识别出早期妊娠并发症的分子预测因子和可修改的危险因素。