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: 10197782
• 负责人: Alison G Lee
• 金额: $ 82.94万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197782
• 关键词: Age; Antioxidants; Asthma; Biological; Biological Process; Birth; Blood Circulation; Boston; Child; Childhood; Cohort Studies; Development; Encapsulated; Endocrine; Enrollment; Environment; 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; Modeling; Molecular; Mothers; Neurosecretory Systems; New York; Newborn Infant; Oscillometry; Outcome; Oxidative Stress; Pathway interactions; Perinatal; Phenotype; Placenta; Plasma; Predisposition; Pregnancy; Prevention strategy; Process; Psychophysiology; RNA Interference; Research; Resistance; Respiration Disorders; 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; 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.

项目摘要 哮喘和肺生长的发育起源开始于子宫内。在确定 终身风险是指导致和维持这种早期易感性的暴露和机制。 我们的研究小组已经建立了产前压力，包括产妇一生的创伤， 喘鸣哮喘肺功能下降我们关注的是创伤经历， 在低收入的少数民族妇女中，特别有可能导致持续的心理生理变化， 都记录了代际效应。然而，母亲的创伤使儿童 与呼吸道疾病的关系还没有很好的描述。喘息/哮喘病理生理学的核心机制 和肺的生长和发育重叠，并涉及一系列事件，包括破坏免疫， 神经内分泌和自主神经功能以及氧化应激。创伤相关的改变在这些关键 女性的调节系统可能持续到怀孕，并损害这些相同的相互关联的 胎儿的呼吸系统，增加未来呼吸系统疾病的风险。胎盘调节 妊娠环境对胎儿通过释放分子信号，包括microRNAs（miRNAs），小 非编码RNA，通过基因表达的表观遗传控制来调节许多生物过程。 胎盘滋养层细胞主动将miRNA分选到细胞外囊泡（EV）中，即，0.05-1? m膜结合的 释放到母体和胎儿循环中的囊泡。EV包裹胎盘的分泌和内容物 miRNAs受子宫内环境应激相关变化的影响。EV包封的miRNAs引发 通过信使RNA（mRNA）沉默改变大基因的基因表达 集.我们利用一项已建立的纵向妊娠队列研究， 创伤、生物库中的母体妊娠中期血浆和静脉脐带血浆以及在 出生，伴有持续呼吸表型（反复喘息和肺功能指数为脉冲 在48个月龄时进行乳房测量（IOS）。我们将调查产妇一生的创伤，EV- 孕中期母体和静脉脐带血浆中包裹的胎盘miRNA， 正常足月分娩（≥ 37周）胎盘和儿童呼吸表型。使用多级 发现和复制与母体创伤和儿童结局相关的胎盘特异性miRNA的方法， 我们可以确定与母亲创伤的代际传递相关的途径， 可能参与规划儿童呼吸道疾病风险。鉴于人们对 EV在妊娠和组织信号传导中的核心作用，我们的发现可能提供一个模型， 扩展到额外的产前风险因素和其他胎儿疾病。