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童年虐待 (CM) 史与 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 (miRNA)，从而为有 CM 病史的人提供自杀风险的分子特征。我们 提出虽然重度抑郁症 (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。早期应激事件引起的表观遗传变化可以引起长期的改变 影响基因网络。 miRNA 表达代表环境的核心机制之一 基因表达的调控。 miRNA 序列本身经过表观遗传修饰。这些的总和 效应可以解释长期的细胞（不良）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物，我们从血浆中分离出神经源性外泌体，并 发现这些外泌体不仅富含大脑表达的 miRNA，而且还表现出一组独特的 与 CM 和自杀相关的 miRNA。还注意到同一组 miRNA 的变化 有 CM 病史的自杀者的大脑中。此外，患有或不患有 CM 的自杀受试者表现出 miRNA 响应急性应激的差异调节，急性应激是自杀行为的短期风险，特别是 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，即存在多个 自杀行为的路径，CM 代表了一条与表达改变和自杀行为相关的独特路径。 一组特定 miRNA 和伴随的下游特定靶基因的表观遗传修饰 网络。为了测试这一点，我们将：1）鉴定一组神经源性外泌体 miRNA，它们与 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 CM 的独立影响 医学博士； 2）检查急性实验应激源是否对神经源性表达有不同的影响 有和没有 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 改变的神经源性外泌体 miRNA 可能导致 CM 相关自杀的机制 行为; 4) 检查 CM 相关 miRNA 的变化是否可以通过其 DNA 的修饰来解释 甲基化。在患有 MDD、自杀、 和 CM 严重程度，我们将测试每个的主要影响，并确定相关的 miRNA 子集 具有自杀倾向和 CM 严重程度。我们还将测试 CM 或自杀倾向对 miRNA 的独立主效应 以及这些因素之间的相互作用。总而言之，使用不同的研究人群，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，可以 在纵向研究中进行测试，2) CM 作为自杀危险因素的潜在机制。