Understanding the transgenerational epigenetic effect of maternal psychosocial trauma exposure on infants via lncRNA-sequencing

通过lncRNA测序了解母亲心理社会创伤暴露对婴儿的跨代表观遗传效应

基本信息

批准号：
10053409
负责人：
Torsten Klengel
金额：
$ 58.13万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-21 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10053409
关键词：
Adult Affect Age Amygdaloid structure Animal Model Anxiety Area Autopsy Behavioral Biological Biological Process Birth Blood Brain Cells Child Child Development Code Cohort Studies Collaborations Collection Communities Country DICER1 gene Data Data Analyses Data Collection Depressed mood Development Early Diagnosis Elderly Emotional Environmental Exposure Epigenetic Process Exposure to Fostering Foundations Future Gene Expression Regulation Generations Genes Genetic Transcription Glucocorticoid Receptor Goals Grant Heritability Hospitals Human Income Infant Infant Development Infrastructure Inherited Institution Knowledge Life Measures Mediating Mediator of activation protein Mental Depression Messenger RNA Modeling Molecular Mothers Mus Newborn Infant Nucleus Accumbens Outcome Parents Pathway interactions Pharmaceutical Preparations Phenotype Play Post-Traumatic Stress Disorders Pregnancy Outcome Prevention Process Proteins Psychological Stress Publications RNA Regulation Regulatory Pathway Research Resources Risk Risk Factors Role Site Visit South Africa Stress Time Tissue-Specific Gene Expression Training Trauma Universities Untranslated RNA Work accomplished suicide base cohort comorbidity differential expression epigenetic regulation growth arrest specific transcript 5 high risk in utero infant outcome interest low and middle-income countries mRNA Expression maternal stress medical schools novel obstetric outcomes offspring postnatal prenatal prenatal exposure prenatal stress prevent prospective psychological outcomes psychosocial receptor sensitivity stress related disorder stressor transcriptome sequencing transgenerational epigenetic inheritance transmission process trauma exposure

Adult Affect Age Amygdaloid structure Animal Model Anxiety Area Autopsy Behavioral Biological Biological Process Birth Blood Brain Cells Child Child Development Code Cohort Studies Collaborations Collection Communities Country DICER1 gene Data Data Analyses Data Collection Depressed mood Development Early Diagnosis Elderly Emotional Environmental Exposure Epigenetic Process Exposure to Fostering Foundations Future Gene Expression Regulation Generations Genes Genetic Transcription Glucocorticoid Receptor Goals Grant Heritability Hospitals Human Income Infant Infant Development Infrastructure Inherited Institution Knowledge Life Measures Mediating Mediator of activation protein Mental Depression Messenger RNA Modeling Molecular Mothers Mus Newborn Infant Nucleus Accumbens Outcome Parents Pathway interactions Pharmaceutical Preparations Phenotype Play Post-Traumatic Stress Disorders Pregnancy Outcome Prevention Process Proteins Psychological Stress Publications RNA Regulation Regulatory Pathway Research Resources Risk Risk Factors Role Site Visit South Africa Stress Time Tissue-Specific Gene Expression Training Trauma Universities Untranslated RNA Work accomplished suicide base cohort comorbidity differential expression epigenetic regulation growth arrest specific transcript 5 high risk in utero infant outcome interest low and middle-income countries mRNA Expression maternal stress medical schools novel obstetric outcomes offspring postnatal prenatal prenatal exposure prenatal stress prevent prospective psychological outcomes psychosocial receptor sensitivity stress related disorder stressor transcriptome sequencing transgenerational epigenetic inheritance transmission process trauma exposure

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项目摘要

SUMMARY PROJECT This collaborative project, between McLean Hospital, Harvard Medical School, USA and Cape Town University, South Africa, proposes to investigate the biological mechanisms underlying effects of maternal stress on infant development. Prospective, longitudinal, mother-child cohort studies have found that children exposed to maternal psychological stress, depression, or anxiety during the prenatal period have higher risk for behavioral and emotional problems later in life, including increased fearfulness, anxiety, and depression. We propose to examine RNA-mediated epigenetic factors in this proposal. We recently found that adults with comorbid PTSD and/or Depression (PTSD/MDD) have reduced expression of the DICER1 gene, which plays a central role in stress-related pathways by controlling ncRNA expression. Additional new work from our group has shown differential expression of a long non-coding RNA (lncRNA), GAS5, which directly regulates glucocorticoid receptor sensitivity, in recently traumatized adults as a predictor of later PTSD development. lncRNAs regulate expression of more than half of all protein-coding genes post-transcriptionally in the body. This study will extend our adult PTSD findings of DICER1, GAS5 and other lncRNA pathways, to elucidate mechanisms underlying transmission of risk across generations using an integrative developmental model in the Drakenstein mother/infant cohort. In aim 1, we will focus on in utero developmental RNA profiles. We will examine lncRNA and lncRNA-mediated epigenetic effects at birth, in infants exposed in utero to maternal PTSD/MDD by investigating RNAs that are altered in both mothers with PTSD/MDD and their infants in the Drakenstein mother/infant cohort (N=450). In aim 2, we will focus on early life developmental RNA profiles. We will examine longitudinal stability of lncRNA-mediated epigenetic factors associated with exposure to maternal PTSD/MDD at birth and at age 2 and 5 years. We will identify lncRNA-based factors that are persistently altered in exposed infants at birth across age 5 to elucidate the effects of maternal stress during early life development, which may prelude to manifestation of negative outcomes later in life. In aim 3, we will focus on early life RNA profiles and subsequent behavioral-developmental outcomes. We will identify the effects of RNA profiles at birth, age 2 and 5 years on behavioral and developmental measures at ages 2, 3.5 and 5 years. In utero and environmentally induced changes in expression levels of RNA-mediated epigenetic factors may predict development of behavioral and emotional problems. Through each of these aims, the proposal will build research capacity through training, site visits, collaborative data analyses, publications, and presentations. Through collaboration between the low- and middle-income country (LMIC) and upper- and middle-income country (UMIC) institutions we will lay foundation via infrastructure and collection of unique phenotypes and RNA-sequencing data for future studies of this unique mother-child cohort in the LMIC, advancing our understanding of risk and child development.

摘要项目这个合作项目，美国哈佛医学院，美国和开普敦之间南非大学提议研究孕产妇的生物学机制对婴儿发育的压力。前瞻性，纵向，母子队列研究发现儿童在产前期间面临母性心理压力，抑郁或焦虑的风险更高后来生活中的行为和情绪问题，包括增加恐惧，焦虑和抑郁。我们建议在此提案中检查RNA介导的表观遗传因子。我们最近发现成年人合并症PTSD和/或抑郁症（PTSD/MDD）的表达降低了DICER1基因的表达，该基因的表达通过控制NCRNA表达，在应力相关途径中的中心作用。我们小组的其他新作品已经显示出长的非编码RNA（lncRNA），GAS5的差异表达，该表达直接调节在最近创伤的成年人中，糖皮质激素受体敏感性是后来PTSD发育的预测指标。 LNCRNA调节体内转录后所有蛋白质编码基因的一半以上的表达。这项研究将扩展我们的DICER1，GAS5和其他LNCRNA途径的成年PTSD发现，以阐明使用综合发展模型在几代人中风险传播的基础机制 Drakenstein母亲/婴儿队列。在AIM 1中，我们将重点关注子宫发育RNA谱。我们将在出生时检查LNCRNA和LNCRNA介导的表观遗传作用，在子宫内暴露于母体的婴儿 PTSD/MDD通过调查PTSD/MDD的两位母亲及其婴儿的RNA都在 Drakenstein母亲/婴儿队列（n = 450）。在AIM 2中，我们将重点关注早期生命发展的RNA谱。我们将检查LNCRNA介导的表观遗传因子与母亲暴露有关的表观遗传因素的纵向稳定性 PTSD/MDD出生时和2岁和5岁。我们将确定基于LNCRNA的因素 5岁时出生时暴露的婴儿改变了，以阐明早期孕产妇压力的影响发展，这可能是在生活后期表现出负面结果的序幕。在AIM 3中，我们将专注于早期生命的RNA谱和随后的行为发展结果。我们将确定RNA的影响出生时，2岁和5岁的行为和发育措施的出生时期，2岁和5岁。在子宫和环境引起的RNA介导的表观遗传因子表达水平的变化可能预测行为和情感问题的发展。通过这些目标，该提议将建立通过培训，现场访问，协作数据分析，出版物和演示文稿的研究能力。通过低收入和中等收入国家以及上层和中等收入之间的合作国家（UMIC）机构我们将通过基础设施和独特表型的收集和收集 RNA序列数据，用于对LMIC中这种独特的母子队列的未来研究，从而推进了我们了解风险和儿童发展。