Maternal trauma, circulating microRNA in extracellular vesicles, and programming of childhood respiratory outcomes

产妇创伤、细胞外囊泡中的循环 microRNA 以及儿童呼吸结局的规划

• 批准号: 10408764
• 负责人: Alison G Lee
• 金额: $ 75.69万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408764
• 关键词: Age; Antioxidants; Asthma; Biological; Biological Process; Birth; Blood Circulation; Boston; Child; Childhood; Cohort Studies; Development; Encapsulated; Endocrine; Enrollment; Epigenetic Process; Event; Fetal Diseases; Fetal Tissues; Fetus; Frequencies; Functional disorder; Future; Gene Expression; Genes; Genetic Transcription; Growth; Growth and Development function; Health; Immune; Impairment; Individual; Inherited; Lead; Life Cycle Stages; Link; Low income; Lung; Lung diseases; Measures; Mediation; Membrane; Messenger RNA; MicroRNAs; Minority Women; Modeling; Molecular; Mothers; Neurosecretory Systems; New York; Newborn Infant; Oscillometry; Outcome; Oxidative Stress; Pathway interactions; Phenotype; Placenta; Plasma; Predisposition; Pregnancy; Prevention strategy; Process; Psychophysiology; RNA Interference; Research; Resistance; Respiration Disorders; Respiratory Disease; Risk; Role; Sampling; Signal Pathway; Signal Transduction; Site; Social Conditions; Stress; System; Term Birth; Therapeutic; Therapeutic Intervention; Tissues; Trauma; United States; Untranslated RNA; Venous; Wheezing; Woman; base; biological adaptation to stress; biomarker identification; circulating microRNA; cohort; deep sequencing; design; differential expression; disorder risk; early detection biomarkers; ethnic minority population; experience; extracellular vesicles; fetal; improved; in utero; indexing; intergenerational; maternal stress; molecular marker; novel; offspring; perinatal development; perinatal environment; prenatal; prenatal risk factor; prenatal stress; pulmonary function; relating to nervous system; respiratory; theories; tissue archive; transmission process; trauma exposure; traumatic stress; trophoblast; vector; vesicular release

PROJECT SUMMARY The developmental origins of asthma and lung growth begin in utero. A critical step in identifying lifelong risk is characterizing exposures and mechanisms that lead to and maintain this early predisposition. Our research team has established links between prenatal stress, including maternal lifetime trauma, and child wheeze, asthma, and reduced lung function. We focus on traumatic experiences, which occur more commonly in lower-income, minority women, are especially likely to lead to persistent psychophysiological alterations, and have documented intergenerational effects. However, pathways by which maternal trauma predispose children to respiratory disease are not well delineated. Mechanisms central to the pathophysiology of wheeze/asthma and lung growth and development overlap and involve a cascade of events that include disrupted immune, neuroendocrine and autonomic function as well as oxidative stress. Trauma-related alterations in these key regulatory systems in women may persist into pregnancy and impair development of these same interrelated systems in the fetus, increasing risk for future respiratory disease. The placenta regulates effects of the gestational milieu on the fetus through the release of molecular signals, including microRNAs (miRNAs), small non-coding RNAs that regulate numerous biological processes through epigenetic control of gene expression. Placental trophoblasts actively sort miRNAs into extracellular vesicles (EVs), i.e., 0.05-1?m membrane-bound vesicles released into maternal and fetal circulations. The secretion and content of EV-encapsulated placental miRNAs are influenced by stress-related changes to the in utero milieu. EV-encapsulated miRNAs prime maternal and fetal tissues via messenger RNA (mRNA) silencing that alters gene expression of large gene sets. We leverage an established longitudinal pregnancy cohort study with measures of maternal lifetime trauma, bio-banked maternal mid-pregnancy plasma and venous cord plasma and placental tissue collected at birth, with ongoing respiratory phenotyping (repeated wheeze and lung function indexed by impulse oscillometry (IOS) at age 48 months). We will investigate associations among maternal lifetime trauma, EV- encapsulated placental miRNAs in maternal mid-pregnancy and venous cord plasma, miRNA/mRNA profiles in placenta from normal term births ( ≥ 37 weeks), and respiratory phenotypes in children. Using a multi-stage approach to discover and replicate placenta-specific miRNAs related to maternal trauma and child outcomes, we may identify pathways associated with intergenerational transmission of maternal trauma and those potentially involved in programming respiratory disease risk in children. Given the evolving understanding of the central role of EVs in pregnancy and tissue signaling, our findings may provide a model that can be extended to additional prenatal risk factors and other fetal disorders.

项目总结 哮喘和肺生长的发育起源于子宫。关键的一步是确定 终身风险是指导致和维持这种早期易感的暴露和机制的特征。 我们的研究团队已经建立了产前应激之间的联系，包括母亲一生的创伤和孩子 喘息、哮喘和肺功能减退。我们关注的是更常见的创伤经历。 在收入较低的少数族裔妇女中，尤其可能导致持续的心理生理变化，以及 有记录在案的代际影响。然而，母亲的创伤使儿童倾向于 对呼吸系统疾病的影响没有很好地描述。喘息/哮喘的主要病理生理学机制 肺的生长和发育重叠，涉及一系列事件，包括免疫功能紊乱， 神经内分泌和自主神经功能以及氧化应激。这些关键部位与创伤相关的改变 女性的监管系统可能会持续到怀孕期间，并损害这些相互关联的相同因素的发育 胎儿体内的系统，增加了未来患呼吸道疾病的风险。胎盘调节 妊娠环境通过释放分子信号对胎儿产生影响，包括microRNAs(MiRNAs)、小分子 非编码RNA，通过表观遗传对基因表达的控制来调节许多生物过程。 胎盘滋养层细胞主动地将miRNAs分选成胞外小泡(EV)，即0.05-1M的膜结合 释放到母体和胎儿循环中的囊泡。肠病毒包裹的胎盘的分泌和含量 MiRNAs受到与压力相关的宫内环境变化的影响。EV封装的miRNAs Prime 通过信使RNA沉默改变大基因基因表达的母婴组织 布景。我们利用一项已建立的纵向妊娠队列研究来衡量母亲的寿命 创伤，生物库中孕妇孕中期血浆和静脉脐带血浆和胎盘组织收集于 出生时，有持续的呼吸表型(反复喘息和肺功能以脉冲为指标 在48个月龄时进行振荡法(IOS)。我们将调查母体终生创伤、EV- 孕中期孕妇胎盘和脐静脉血浆中的miRNA/mR-NA谱 正常足月出生的胎盘(≥37周)和儿童的呼吸表型。使用多阶段 发现和复制与母体创伤和儿童结局有关的胎盘特异性miRNA的方法， 我们可以确定与母体创伤代际传播相关的途径，以及 可能参与规划儿童的呼吸系统疾病风险。鉴于对…的不断发展的理解 EVS在妊娠和组织信号转导中的核心作用，我们的发现可能提供一个模型，可以 扩大到其他产前风险因素和其他胎儿疾病。