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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：
10663843
负责人：
Torsten Klengel
金额：
$ 57.91万
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/10663843
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 Environment 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 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 Suicide Time Tissue-Specific Gene Expression Training Trauma Universities Untranslated RNA Work behavior prediction 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 posttranscriptional 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

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.

项目概要该合作项目由美国哈佛医学院麦克莱恩医院和开普敦合作南非大学提议调查孕产妇影响的生物学机制对婴儿发育造成压力。前瞻性、纵向、母子队列研究发现，儿童在产前期间，母亲受到心理压力、抑郁或焦虑的影响，患此病的风险较高。晚年的行为和情绪问题，包括恐惧、焦虑和抑郁的增加。我们提议在该提案中检查 RNA 介导的表观遗传因素。我们最近发现成年人共病 PTSD 和/或抑郁症 (PTSD/MDD) 会降低 DICER1 基因的表达，该基因在通过控制 ncRNA 表达在应激相关途径中发挥核心作用。我们小组的其他新作品已经显示出长非编码 RNA (lncRNA) GAS5 的差异表达，它直接调节糖皮质激素受体敏感性，在最近遭受创伤的成年人中作为后期 PTSD 发展的预测因子。 lncRNA 在体内转录后调节超过一半的蛋白质编码基因的表达。这项研究将扩展我们对 DICER1、GAS5 和其他 lncRNA 通路的成人 PTSD 发现，以阐明使用综合发展模型研究风险跨代传递的机制德拉肯斯坦母亲/婴儿队列。在目标 1 中，我们将重点关注子宫内发育 RNA 谱。我们将检查出生时暴露于母体的婴儿的 lncRNA 和 lncRNA 介导的表观遗传效应 PTSD/MDD 通过调查患有 PTSD/MDD 的母亲及其婴儿体内发生改变的 RNA Drakenstein 母亲/婴儿队列 (N=450)。在目标 2 中，我们将重点关注生命早期发育的 RNA 谱。我们将检查与母体接触相关的 lncRNA 介导的表观遗传因素的纵向稳定性出生时、2 岁和 5 岁时患有 PTSD/MDD。我们将确定持续存在的基于 lncRNA 的因素 5 岁出生时暴露的婴儿发生变化，以阐明母亲压力在生命早期的影响发展，这可能预示着以后生活中出现负面结果。在目标 3 中，我们将重点关注早期生命 RNA 谱和随后的行为发育结果。我们将确定 RNA 的影响出生、2 岁和 5 岁时关于 2、3.5 和 5 岁时行为和发育测量的概况。在子宫内和环境引起的 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绪问题的发展。通过这些目标中的每一个，该提案将建立通过培训、实地考察、协作数据分析、出版物和演示来提高研究能力。通过低收入和中等收入国家（LMIC）与高收入和中等收入国家之间的合作我们将通过基础设施和收集独特表型和 RNA 测序数据用于中低收入国家这一独特母子队列的未来研究，推进我们的研究了解风险和儿童发展。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dimensional clinical phenotyping using post-mortem brain donor medical records: post-mortem RDoC profiling is associated with Alzheimer's disease neuropathology.

DOI：
10.1002/dad2.12464
发表时间：
2023-07
期刊：
Alzheimer's & dementia (Amsterdam, Netherlands)
影响因子：
0
作者：
通讯作者：

Genetic structure correlates with ethnolinguistic diversity in eastern and southern Africa.

DOI：
10.1016/j.ajhg.2022.07.013
发表时间：
2022-09-01
期刊：
American journal of human genetics
影响因子：
9.8
作者：
通讯作者：

Gene expression in cord blood links genetic risk for neurodevelopmental disorders with maternal psychological distress and adverse childhood outcomes.

DOI：
10.1016/j.bbi.2018.05.016
发表时间：
2018-10
期刊：
Brain, behavior, and immunity
影响因子：
0
作者：
Breen MS;Wingo AP;Koen N;Donald KA;Nicol M;Zar HJ;Ressler KJ;Buxbaum JD;Stein DJ
通讯作者：
Stein DJ

Gene expression in the dorsolateral and ventromedial prefrontal cortices implicates immune-related gene networks in PTSD.

DOI：
10.1016/j.ynstr.2021.100398
发表时间：
2021-11
期刊：
Neurobiology of stress
影响因子：
5
作者：
Logue MW;Zhou Z;Morrison FG;Wolf EJ;Daskalakis NP;Chatzinakos C;Georgiadis F;Labadorf AT;Girgenti MJ;Young KA;Williamson DE;Zhao X;Grenier JG;Traumatic Stress Brain Research Group;Huber BR;Miller MW
通讯作者：
Miller MW

Genomic factors underlying sex differences in trauma-related disorders.