Neural-Derived Plasma Exosomal MicroRNAs As Promising Novel Biomarkers for Suicidality and Treatment Outcome in Adolescents

神经源性血浆外泌体 MicroRNA 作为青少年自杀和治疗结果的有前景的新型生物标志物

• 批准号: 10684830
• 负责人: Yogesh Dwivedi
• 金额: $ 74万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684830
• 关键词: Adolescent; Adolescent and Young Adult; Adult; Affect; Aftercare; Age; Aggressive behavior; Antidepressive Agents; Biological; Biological Markers; Blood; Brain; Cause of Death; Child; Child Abuse and Neglect; Clinical; Data; Data Set; Development; Diagnosis; Disease; Feeling suicidal; Future; Gene Expression; Gene Targeting; Genes; Hostility; Impulsivity; Individual; Ketamine; Major Depressive Disorder; Maps; Mediator; Mental Depression; Mental disorders; MicroRNAs; Molecular; Moods; Neurons; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Plasma; Population; Prevalence; Psychopathology; Public Health; Recording of previous events; Regulator Genes; Regulatory Pathway; Reporting; Risk; Suicide; Suicide attempt; Suicide prevention; Testing; Transducers; Treatment outcome; Untranslated RNA; Variant; Youth; adolescent suicide; age group; biosignature; differential expression; disorder risk; exosome; genome-wide; improved; interest; neural; new therapeutic target; novel; novel marker; novel strategies; peripheral blood; posttranscriptional; prevent; response; suicidal; suicidal adolescent; suicidal patient; suicidal risk; suicide rate; tool; tool development; trait; treatment response

Suicide is the 2nd leading cause of death in adolescents. Unfortunately, our ability to accurately predict suicidal ideation (SI) and suicide attempts (SA) among adolescents remains remarkably limited. Thus, there is an urgent need for biomarkers that can identify risk for SI and SA. There is also a need to identify novel molecular pathways that may underlie suicide risk. There is growing interest in microRNAs (miRNAs), a subclass of non-coding RNAs that regulate mRNA expression via post-transcriptional mechanisms, as potential mediators of disease pathologies and in the development of targeted novel therapeutics. Earlier, we reported that specific miRNAs were markedly altered in the brain of adults who died by suicide independent of psychiatric illnesses, suggesting that miRNAs can distinguish suicidality separately from psychopathology. Using a specific neural marker, we isolated neural-derived exosomes (NDEs) from blood plasma and found that these exosomes are highly enriched with miRNAs that are expressed in the brain. In preliminary studies, we also found remarkable resemblance in brain and NDE miRNA changes among adult and adolescent suicide populations. Differences in many miRNAs were common in adults and adolescents with SI or SA; however, a distinct set of miRNAs was associated exclusively with adolescent suicide. In addition, differentially expressed NDE miRNAs changed significantly in adults treated with ketamine. Our novel approach thus provides a unique opportunity to detect NDE miRNAs in plasma, which can be used as biomarkers for suicidality and treatment response. Based on our pilot data, we propose an overarching hypothesis that a subset of NDE miRNAs will be differentially expressed in adolescents with MDD and SI or SA compared with non-suicidal adolescents with MDD and healthy controls. There will be unique subsets of miRNAs specifically associated with MDD, SI, and SA. These miRNAs will have specific mRNA targets and biological pathways that may be associated with SI, SA, and MDD risk. To test these, we will examine genome-wide expression of NDE miRNAs and mRNAs in the following groups of adolescent subjects (11-19 y; n=240): 1) MDD with serious SI and a recent SA (MDD+SA), 2) MDD+SI without recent SA, 3) MDD without recent SI or SA (MDD-SI/SA), and 4) healthy controls without a history of mental disorder. We will also test if expression of NDE miRNAs will change across six weeks of antidepressant treatment (AD). With this, we will examine if: 1) specific subset(s) of NDE miRNAs are associated with SI and SA among adolescents, 2) specific miRNA/mRNA-regulatory pathway is associated with SI, SA, and MDD, and 3) response to AD treatment impacts differences in NDE miRNAs associated with MDD and SI/SA. Using our existing NDE miRNA datasets in 240 adults ages 20-65 y across the same groups proposed for this study, we will also examine if miRNA biosignatures are common in MDD and SI/SA groups for adolescents and adults, or if they differ by age. Altogether, our study will provide novel avenues to identify miRNAs as ‘‘molecular tools’’ for the development of a biomarker for suicidality across age group and eventually new molecular-based therapies to treat or prevent this disorder.

不幸的是，我们无法准确预测自杀行为。 青少年的意念（SI）和自杀企图（SA）仍然非常有限，因此，有一个紧迫的问题。 需要能够识别 SI 和 SA 风险的生物标志物 还需要识别新的分子途径。 人们对非编码 RNA 的一个亚类 microRNA (miRNA) 越来越感兴趣。 通过转录后机制调节 mRNA 表达，作为疾病的潜在介质 在病理学和靶向新疗法的开发中，我们报道了特定的 miRNA 独立于精神疾病而自杀的成年人的大脑中显着存在这种现象，这表明 我们使用特定的神经标记物可以将自杀与精神病理学区分开来。 从血浆中分离出神经源性外泌体（NDE），并发现这些外泌体高度富集 在初步研究中，我们还发现了与大脑中表达的 miRNA 的显着相似之处。 成人和青少年自杀人群的大脑和濒死体验 miRNA 变化 许多 miRNA 存在差异。 在患有 SI 或 SA 的成人和青少年中很常见；然而，一组不同的 miRNA 与之相关； 此外，差异表达的 NDE miRNA 在 因此，我们的新方法提供了检测 NDE miRNA 的独特机会。 根据我们的试点数据，我们可以将其用作自杀和治疗反应的生物标志物。 提出一个总体假设，即 NDE miRNA 的子集将在青少年中差异表达 患有 MDD 和 SI 或 SA 的患者与患有 MDD 的非自杀青少年和健康对照者相比。 与 MDD、SI 和 SA 特异性相关的独特 miRNA 子集 这些 miRNA 将具有特定的 mRNA。 为了测试这些，我们将检查可能与 SI、SA 和 MDD 风险相关的目标和生物途径。 以下青少年受试者组（11-19 岁； n=240): 1) MDD 有严重的 SI 和最近的 SA (MDD+SA), 2) MDD+SI 没有最近的 SA, 3) MDD 没有 最近的 SI 或 SA (MDD-SI/SA)，以及 4) 没有精神障碍病史的健康对照我们还将测试是否。 NDE miRNA 的表达将在六周的抗抑郁治疗 (AD) 中发生变化。 检查是否：1) NDE miRNA 的特定子集与青少年中的 SI 和 SA 相关，2) 特定的 miRNA/mRNA 调节途径与 SI、SA 和 MDD 相关，3) 对 AD 治疗影响的反应 使用我们现有的 240 个 NDE miRNA 数据集与 MDD 和 SI/SA 相关的 NDE miRNA 的差异。 年龄 20-65 岁的成年人在本研究提出的同一组中，我们还将检查 miRNA 生物特征是否 在青少年和成人的 MDD 和 SI/SA 群体中很常见，或者如果它们总体上因年龄而异。 将为识别 miRNA 作为开发生物标志物的“分子工具”提供新途径 跨年龄组的自杀，最终出现新的分子疗法来治疗或预防这种疾病。