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

自杀是青少年死亡的第二大原因。不幸的是，我们准确预测自杀的能力 青少年的自杀意念（SI）和自杀企图（SA）仍然非常有限。因此，迫切需要 需要能够识别SI和SA风险的生物标志物。还需要确定新的分子途径 可能是自杀风险的基础。microRNA（miRNAs）是非编码RNA的一个亚类， 通过转录后机制调节mRNA表达，作为疾病的潜在介质 病理学和靶向新疗法的发展。早些时候，我们报道了特定的miRNAs 在与精神疾病无关的自杀死亡的成年人的大脑中， miRNAs可以区分自杀倾向和精神病理学。使用一种特定的神经标记，我们 从血浆中分离出神经源性外泌体（NDEs），发现这些外泌体高度富集 与大脑中表达的miRNAs结合。在初步研究中，我们还发现了 成人和青少年自杀人群中脑和NDE miRNA的变化。许多miRNA的差异 在SI或SA的成年人和青少年中很常见;然而，一组独特的miRNAs与SI或SA相关。 专门针对青少年自杀此外，差异表达的NDE miRNAs在不同的细胞中也有显著变化。 服用氯胺酮的成年人因此，我们的新方法提供了一个独特的机会，检测NDE的miRNA， 血浆，其可用作自杀倾向和治疗反应的生物标志物。根据我们的试点数据，我们 提出一个总体假设，即NDE miRNA的一个子集在青少年中差异表达 与非自杀的MDD青少年和健康对照组相比。会有 与MDD、SI和SA特异性相关的miRNA的独特子集。这些miRNAs会有特定的mRNA 可能与SI、SA和MDD风险相关的靶点和生物学途径。为了验证这些，我们将检查 NDE miRNAs和mRNAs在以下青少年受试者组中的全基因组表达（11 - 19岁; n = 240）：1）MDD伴严重SI和近期SA（MDD + SA），2）MDD + SI，近期无SA，3）MDD无 近期SI或SA（MDD-SI/SA），和4）无精神障碍史的健康对照。我们还将测试 NDE miRNA的表达将在抗抑郁治疗（AD）的六周内发生变化。有了这个， 检查：1）NDE miRNAs的特定子集是否与青少年中的SI和SA相关，2）特定的 miRNA/mRNA调节通路与SI、SA和MDD相关，以及3）对AD治疗影响的反应 与MDD和SI/SA相关的NDE miRNA的差异。使用我们现有的NDE miRNA数据集， 对于年龄在20 - 65岁之间的成年人，我们也将检查miRNA生物特征， 在青少年和成人的MDD和SI/SA组中很常见，或者如果它们因年龄而异。总之，我们的研究 将提供新的途径来鉴定miRNA作为开发生物标志物的"分子工具"， 自杀倾向的年龄组，并最终新的分子为基础的疗法，以治疗或预防这种疾病。

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.