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

这是美国埃默里大学和开普敦大学(UCT)于 南非的一位科学家建议研究人类免疫缺陷的跨代效应的生物学机制。 胎儿期暴露于母体心理压力、焦虑或抑郁。我们建议对后代进行检查 在这项提议中，基因表达是这种代际联系的潜在贡献者。 已有研究表明，胎儿大脑发育的很大一部分发生在产前，而这一过程 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 精神障碍(PTSD)和抑郁症降低了DICER1和部分下游microRNAs的表达 (MiRNAs)。这种应激相关的DICER1/miRNA调节通路在血液和脑中似乎是一致的 人类和老鼠的模型。我们推测，这种与压力相关的调节途径也在 胎儿期母亲创伤后应激障碍和/或抑郁(PNM-PTSD/Dep)。我们建议 通过三个目标扩展我们在Drakenstein母子二人组中的发现。 在目标1中，我们计划比较DICER1的表达以及全基因组的基因表达谱 子女病例(暴露于PNM-PTSD/DEP)和出生时没有暴露于此类暴露的子女对照。在目标2中， 我们建议检查出生时子女病例和对照组之间的全基因组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 在这种代际联系的基础上。 通过这些目标中的每一个，该提案将通过培训、现场访问、合作 数据分析、出版物和演示文稿。虽然中低收入(LMIC)网站在 基因组学研究，它在分析基因表达数据方面的能力很小；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LMIC背景下，这一独特的母子队列。

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.