MicroRNA Correlates of Childhood Maltreatment and Suicidality

该项目的目的是确定儿童期虐待史(CM)与 自杀风险与特定基因表达的改变和表观遗传修饰有关 MicroRNAs(MiRNAs)，从而为有CM病史的人提供自杀风险的分子标记。我们 虽然重度抑郁障碍(MDD)和自杀倾向都是复杂的表型，但CM改变了 两者的风险门槛都是如此。早期应激事件引起的表观遗传变化可导致长期的改变 影响基因网络。MiRNA的表达是环境胁迫的核心机制之一 基因表达的调控。MiRNA序列本身是表观遗传修饰的。这些因素的总和 影响可能解释长期的细胞(不良)适应，这可能导致CM的自杀易感性。 人口。使用一种特定的细胞表面标记，我们从血浆和 发现这些外切体不仅富含大脑表达的miRNAs，而且还表现出一套独特的 与心肌梗死和自杀有关的miRNAs。还注意到同一组miRNAs的变化 在有CM病史的自杀受试者的大脑中。此外，有和没有CM的自杀受试者都显示出 MiRNAs对急性应激反应的差异调节，这是自杀行为的短期风险，特别是在 CM的上下文。此外，miRNA表达的变化与外体miRNA启动子高度相关。 甲基化。基于我们的初步数据，我们提出了一个总体假设，即有多个 自杀行为的路径，而CM代表与改变的表达和 一组特定的miRNAs和伴随的下游特定靶基因的表观遗传修饰 网络(S)。为了测试这一点，我们将：1)鉴定一组神经来源的外体miRNAs，它们与 自杀倾向与CM严重程度的交互作用，同时控制自杀、CM和 MDD；2)检查急性实验应激源是否对神经源的表达产生不同影响 伴和不伴CM的自杀患者的外体miRNAs；3)使用生物信息学工具检测潜在的 神经源性外体miRNAs改变可能参与CM相关自杀的机制 行为；以及4)检查与CM相关的miRNAs的变化是否通过其DNA的修改来解释 甲基化。在参与者(n=450；在350名受试者队列中重复)中，涉及MDD、自杀、 和CM严重性，我们将测试每个因素的主要影响，并确定关联的miRNAs子集 有自杀倾向和严重的心肌梗塞。我们还将测试CM或自杀对miRNAs的独立主要影响 以及这些因素之间的相互作用。总之，使用一个独特的研究群体，独特的神经来源 血浆外切体，以及创新的分子、生物统计学和生物信息学工具，我们的研究将确定：1) 神经源性血浆外体miRNAs作为CM背景下自杀风险的新生物标志 在纵向研究中进行测试，以及2)CM可作为自杀危险因素的潜在机制。

The purpose of this project is to determine if the relationship between a history of childhood maltreatment (CM) and suicide risk is associated with alterations in the expression and epigenetic modification of specific microRNAs (miRNAs), thereby providing a molecular signature of suicide risk in people with a history of CM. We propose that whereas both major depressive disorder (MDD) and suicidality are complex phenotypes, CM alters the risk threshold for both. Epigenetic changes caused by early stressful events can induce long-term alterations affecting networks of genes. miRNA expression represents one of the central mechanisms for environmental regulation of gene expression. miRNA sequences themselves are epigenetically modified. The sum of these effects may explain long-term cellular (mal)adaptations which may lead to suicide vulnerability in the CM population. Using a specific cell surface marker, we isolated neural-derived exosomes from blood plasma and found that these exosomes were not only enriched with brain expressed miRNAs, but also showed a unique set of miRNAs that were associated with CM and suicidality. Changes in the same set of miRNAs were also noted in the brain of suicide subjects with a history of CM. In addition, suicidal subjects with and without CM showed differential regulation of miRNAs in response to acute stress, a short-term risk for suicidal behavior, particulay in the context of CM. Moreover, miRNA expression changes were highly correlated with exosomal miRNA promoter methylation. Based on our preliminary data, we propose an overarching hypothesis that there are multiple paths to suicidal behavior, and CM represents a unique path that is associated with altered expression and epigenetic modification of a specific set of miRNAs and concomitant downstream specific target genes and network(s). To test this, we will: 1) identify a set of neural-derived exosomal miRNAs that are associated with the interaction of suicidality and CM severity while controlling for the independent effects of suicidality, CM, and MDD; 2) examine whether an acute experimental stressor differentially impacts the expression of neural-derived exosomal miRNAs in suicidal patients with and without CM; 3) use bioinformatic tools to examine potential mechanisms by which altered neural-derived exosomal miRNAs may contribute to CM-associated suicidal behavior; and 4) examine if changes in CM-associated miRNAs are explained by modifications in their DNA methylation. In participants (n=450; replicated in a cohort of 350 subjects) across the spectrum of MDD, suicide, and CM severity, we will test for the main effects of each, and identify a subset of miRNAs that are associated with suicidality and CM severity. We will also test for the independent main effects of CM or suicidality on miRNAs and the interactions among those factors. Altogether, using a distinct study population, unique neural-derived plasma exosomes, and innovative molecular, biostatistical, and bioinformatic tools, our study will identify: 1) neural-derived plasma exosomal miRNAs as a novel biosignature of suicide risk in the context of CM that can be tested in longitudinal studies, and 2) potential mechanisms by which CM can act as a risk factor for suicidality.