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，我们准确预测自杀倾向的能力 青少年的意念(SI)和自杀企图(SA)仍然非常有限。因此，有一个紧急的 需要能够识别SI和SA风险的生物标记物。还需要确定新的分子途径 这可能是自杀风险的基础。人们对微RNA(MiRNAs)的兴趣与日俱增，这是非编码RNA的一个子类 通过转录后机制调节mRNA的表达，作为疾病的潜在媒介 在病理学和靶向新疗法的开发方面。早些时候，我们报道了特定的miRNAs 在没有精神疾病的情况下自杀死亡的成年人的大脑发生了显著的变化，这表明 MiRNAs可以区分自杀和精神病态。使用一种特定的神经标志物，我们 从血浆中分离神经源性外切体(NDE)，发现这些外切体高度浓缩 大脑中表达的miRNAs。在初步研究中，我们还发现在 成人和青少年自杀人群中脑和NDE miRNA的变化。许多miRNAs的差异 在患有SI或SA的成年人和青少年中很常见；然而，一组不同的miRNAs与 完全与青少年自杀有关。此外，差异表达的NDE miRNAs在 用氯胺酮治疗的成年人。因此，我们的新方法提供了一个独特的机会来检测NDE miRNA 血浆，可作为自杀和治疗反应的生物标志物。根据我们的试点数据，我们 提出一个压倒一切的假设，即NDE miRNAs的子集在青少年中会有差异表达 患有MDD和SI或SA的青少年与非自杀的MDD青少年和健康对照组进行比较。会有 与MDD、SI和SA特定关联的miRNAs的唯一子集。这些miRNAs将具有特定的mRNA 可能与SI、SA和MDD风险相关的靶点和生物途径。为了测试这些，我们将检查 NDE miRNAs和mRNAs在以下青春期受试者组中的全基因组表达(11-19岁； N=240)：1)有严重SI和近期SA的MDD(MDD+SA)，2)无近期SA的MDD+SI，3)无 最近的SI或SA(MDD-SI/SA)，以及4)无精神障碍史的健康对照。我们还将测试是否 NDE miRNAs的表达将在抗抑郁药物治疗(AD)的六周内发生变化。有了这个，我们将 研究：1)NDE miRNAs的特定子集(S)是否与青少年中的SI和SA相关，2)特异性 MiRNA/mRNA调节通路与SI、SA和MDD相关；3)对AD治疗的反应 与MDD和SI/SA相关的NDE miRNAs的差异。在240中使用我们现有的NDE miRNA数据集 在这项研究的同一组20-65岁的成年人中，我们还将检查miRNA生物签名 在青少年和成人的MDD和SI/SA组中很常见，或者如果他们因年龄而不同。总而言之，我们的研究 将提供新的途径来识别miRNAs作为开发生物标记物的分子工具 整个年龄段的自杀倾向，最终有新的基于分子的疗法来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.