Transgenerational Effects of Maternal Stressors: Investigating the Role of Infant Gene Expression

母体应激源的跨代效应：研究婴儿基因表达的作用

• 批准号: 10222520
• 负责人: Nastassja Koen
• 金额: $ 22.63万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222520
• 关键词: African; Amygdaloid structure; Anxiety; Autopsy; Behavioral; Biological; Birth; Blood; Brain; Child; Child Health; Chromatin; Code; Cohort Studies; Collaborations; Collection; DICER1 gene; DNA Damage; Data; Data Analyses; Data Collection; Depressed mood; Development; Early Diagnosis; Emotional; Environment; Environmental Exposure; Enzymes; Exposure to; Fostering; Foundations; Future; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Gene set enrichment analysis; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Grant; Income; Individual; Infant; Infrastructure; Innate Immune Response; Knowledge; Life; Mediating; Mental Depression; Messenger RNA; MicroRNAs; Molecular; Mothers; Mus; Nucleus Accumbens; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Population; Population Genetics; Post-Traumatic Stress Disorders; Pregnancy Outcome; Prevention; Process; Proteins; Psychological Stress; Publications; RNA; Regulation; Research; Research Personnel; Role; Site; Site Visit; Small RNA; South Africa; South African; Stress; Suicide; Synapses; Tissue-Specific Gene Expression; Tissues; Training; Trauma; Universities; Work; case control; cohort; differential expression; epigenetic regulation; fetal; genome-wide; high risk; human model; insight; intergenerational; mRNA Expression; mouse model; neurobiological mechanism; obstetric outcomes; offspring; peripheral blood; postnatal; prenatal; prospective; response; stressor; transcriptome sequencing

This collaborative project, between Emory University in the USA and the University of Cape Town (UCT) in South Africa, proposes to investigate biological mechanisms underlying the transgenerational effects of exposure to prenatal maternal psychological stress, anxiety, or depression. We propose to examine offspring gene expression as a potential contributor to this intergenerational association in this proposal. It has been suggested that a significant portion of fetal brain development occurs prenatally and this process may be influenced by maternal environment. Our recent work found that individuals with posttraumatic stress disorder (PTSD) and depression have reduced expression of DICER1 and selected downstream microRNAs (miRNAs). This stress-related DICER1/miRNA regulation pathway seems consistent in blood and brain in humans and mouse models. We hypothesize that this stress-related regulation pathway is also at play in young children being exposed to prenatal maternal PTSD and/or depression (PnM-PTSD/dep). We propose to extend our findings in the Drakenstein mother/child dyads through three aims. In Aim 1 we plan to compare DICER1 expression as well as genome-wide gene expression profiles between offspring cases (exposed to PnM-PTSD/dep) and offspring controls with no such exposure at birth. In Aim 2, we propose to examine genome-wide miRNA expression profiles between offspring cases and controls at birth. Through these aims, we hope to identify genes and pathways potentially implicated in the mechanisms underlying this intergenerational association. Through each of these aims, the proposal will build research capacity through training, site visits, collaborative data analyses, publications, and presentations. While the low-middle income (LMIC) site has some capacity in genomics research, it has very little capacity in the analysis of gene expression data; this grant will play a key role in building such capacity. Through collaboration between the LMIC and high-income investigators, we will lay the foundation - via infrastructure and collection of unique phenotypes and RNA data - for future studies of this unique mother-child cohort in the LMIC context.

美国埃默里大学和南非开普敦大学（UCT）之间的这一合作项目 南非，建议调查生物学机制的跨代影响， 暴露于产前母体心理压力、焦虑或抑郁。我们建议检查后代 基因表达作为这种代际关联的潜在贡献者。 有人认为，胎儿大脑发育的重要部分发生在产前，这一过程 可能受母体环境的影响。我们最近的研究发现患有创伤后应激障碍的人 创伤后应激障碍（PTSD）和抑郁症的DICER 1和选定的下游microRNA的表达减少 （miRNAs）。这种应激相关的DICER 1/miRNA调节途径在血液和大脑中似乎是一致的， 人类和小鼠模型。我们推测，这种与压力相关的调节途径也在调节神经元的功能。 幼儿暴露于产前母体PTSD和/或抑郁症（PnM-PTSD/dep）。我们建议 通过三个目标扩展我们在德拉肯斯坦母子二人组中的发现。 在目标1中，我们计划比较DICER 1表达以及全基因组基因表达谱， 后代病例（暴露于PnM-PTSD/dep）和出生时未暴露于PnM-PTSD/dep的后代对照。在目标2中， 我们建议在出生时检查子代病例和对照之间的全基因组miRNA表达谱。 通过这些目标，我们希望确定可能与这些机制有关的基因和途径 这种代际关联的基础。 通过这些目标中的每一个，该提案将通过培训、实地考察、合作和培训来建立研究能力。 数据分析、出版物和演示文稿。虽然中低收入（LMIC）网站有一定的能力， 在基因组学研究方面，它在基因表达数据分析方面的能力非常有限;这笔赠款将发挥关键作用。 在建设这种能力方面发挥作用。通过LMIC和高收入调查人员之间的合作，我们将 通过基础设施和收集独特的表型和RNA数据，为未来的研究奠定基础。 在低收入国家的背景下，这一独特的母婴群体。