MicroRNA Correlates of Childhood Maltreatment and Suicidality

MicroRNA 与童年虐待和自杀的相关性

• 批准号: 10394212
• 负责人: Yogesh Dwivedi
• 金额: $ 66.74万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-16 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10394212
• 关键词: Acute; Affect; Aggressive behavior; Autopsy; Biometry; Brain; Cell surface; Cells; Characteristics; Child Abuse and Neglect; Complex; DNA Methylation; Data; Depression and Suicide; Epigenetic Process; Exhibits; Feeling suicidal; Gene Expression; Gene Expression Regulation; Hostility; Human; Impulsivity; Lead; Link; Longitudinal Studies; Major Depressive Disorder; Mediator of activation protein; Methods; Methylation; MicroRNAs; Modification; Molecular; Molecular Profiling; Participant; Pathologic; Pathway interactions; Patient Recruitments; Patients; Pattern; Persons; Phenotype; Plasma; Population; Recording of previous events; Regulation; Regulator Genes; Risk; Risk Factors; Severities; Stressful Event; Suicide; Suicide attempt; Sum; Synapses; Test Result; Testing; Transducers; Trier Social Stress Test; Work; acute stress; base; bioinformatics tool; biosignature; clinical phenotype; cohort; exosome; gene network; ideation; innovation; neural network; novel; peripheral blood; promoter; psychological stressor; relating to nervous system; response; stressor; study population; suicidal; suicidal behavior; suicidal patient; suicidal risk; suicide brain

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.

该项目的目的是确定儿童虐待史（CM）之间的关系是否存在 自杀风险与特定表达和表观遗传修饰有关 MicroRNA（miRNA），从而为有CM史的人提供了自杀风险的分子特征。我们 提出，尽管主要抑郁症（MDD）和自杀性都是复杂的表型，但CM改变了 两者的风险阈值。早期压力事件引起的表观遗传变化可以引起长期变化 影响基因网络。 miRNA表达代表环境的中心机制之一 基因表达的调节。 miRNA序列本身是表观遗传修饰的。这些总和 效果可能解释了长期的细胞（MAL）适应，这可能导致CM的自杀脆弱性 人口。使用特定的细胞表面标记，我们从血浆和 发现这些外泌体不仅富含大脑表达的miRNA，而且还显示了独特的集合 与CM和自杀性相关的miRNA。还注意到同一组miRNA中的变化 在具有CM病史的自杀受试者的大脑中。此外，有和没有CM的自杀受试者显示 响应急性应激的miRNA调节，自杀行为的短期风险，特别是 CM的上下文。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代表与改变的表达和变化相关的独特路径 一组特定的miRNA和伴随的下游特定靶基因的表观遗传修饰，以及 网络。为了测试这一点，我们将：1）确定一组与 自杀性和CM严重程度的相互作用在控制自杀，CM和 MDD; 2）检查急性实验压力源是否会差异地影响神经衍生的表达 有或没有CM的自杀患者的外泌体miRNA； 3）使用生物信息学工具检查潜力 改变神经衍生的外泌体miRNA可能有助于CM相关自杀的机制 行为; 4）检查是否通过DNA的修饰来解释与CM相关的miRNA的变化 甲基化。在参与者（n = 450；在350名受试者的队列中复制），自杀，自杀， 和cm的严重程度，我们将测试每种的主要影响，并确定相关的miRNA子集 具有自杀性和CM严重性。我们还将测试CM或自杀性对miRNA的独立主要影响 以及这些因素之间的相互作用。总共使用独特的研究人群，独特的神经衍生 血浆外泌体以及创新的分子，生物统计和生物信息学工具，我们的研究将识别：1） 神经来源的血浆外泌体miRNA作为自杀风险的一种新型生物签名，可以在CM的背景下 在纵向研究中进行测试，以及2）CM可以作为自杀性的危险因素的潜在机制。