MicroRNA Correlates of Childhood Maltreatment and Suicidality

本项目的目的是确定是否有儿童虐待史（CM） 而自杀风险与特定基因的表达和表观遗传修饰的改变有关， microRNA（miRNAs），从而提供了一个分子签名的自杀风险的人与CM的历史。我们 我提出，尽管重度抑郁症（MDD）和自杀倾向都是复杂的表型，但CM改变了 两者的风险阈值。由早期应激事件引起的表观遗传学改变可诱导长期改变 影响基因网络。小RNA表达是环境调节的核心机制之一， 基因表达的调控。miRNA序列本身是表观遗传修饰的。之和 这些效应可以解释长期的细胞（mal）适应，这可能导致CM中的自杀脆弱性 人口使用特定的细胞表面标记，我们从血浆中分离出神经源性外泌体， 发现这些外泌体不仅富含大脑表达的miRNA，而且还显示出一组独特的 与CM和自杀倾向相关的miRNAs。在同一组miRNAs的变化也被注意到 有CM病史的自杀者的大脑中此外，有自杀倾向的受试者和无自杀倾向的受试者显示， miRNAs在急性应激反应中的差异调节，这是自杀行为的短期风险，特别是在 CM的背景。此外，miRNA表达变化与外泌体miRNA启动子高度相关 甲基化根据我们的初步数据，我们提出了一个总体假设，即有多个 自杀行为的途径，CM代表了一条与表达改变相关的独特途径， 一组特定的miRNA和伴随的下游特定靶基因的表观遗传修饰， 网络。为了验证这一点，我们将：1）鉴定一组神经源性外泌体miRNA，其与以下相关： 自杀倾向和CM严重程度的相互作用，同时控制自杀倾向、CM和 MDD; 2）检查急性实验性应激源是否差异性地影响神经源性应激蛋白的表达。 外泌体miRNA在有和没有CM的自杀患者中的表达; 3）使用生物信息学工具来检查可能的 改变的神经源性外泌体miRNA可能有助于CM相关自杀的机制 行为;以及4）检查CM相关miRNA的变化是否可以通过其DNA中的修饰来解释 甲基化在参与者（n=450;在350例受试者的队列中重复）中， 和CM的严重程度，我们将测试每一个的主要影响，并确定一个子集的miRNA， 有自杀倾向和严重CM我们还将测试CM或自杀倾向对miRNAs的独立主效应， 以及这些因素之间的相互作用。总之，使用不同的研究人群，独特的神经源性 血浆外泌体和创新的分子，生物统计和生物信息学工具，我们的研究将确定：1） 神经源性血浆外泌体miRNA作为CM背景下自杀风险的新生物特征， 在纵向研究中进行测试，和2）CM可以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.