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; 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.

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 青少年中的构想（SI）和自杀企图（SA）仍然非常有限。那是紧急的 需要可以识别SI和SA风险的生物标志物。还需要识别新的分子途径 这可能是自杀风险的基础。对MicroRNA（miRNA）的兴趣越来越大，这是一个非编码RNA的子类 通过转录后机制来调节mRNA的表达，作为疾病的潜在介体 病理和有针对性的新型疗法的发展。早些时候，我们报道了特定的miRNA 在独立于精神病的自杀死亡的成年人的大脑中，大脑发生了明显改变，这表明 miRNA可以将自杀性与精神病理学分开区分。使用特定的神经标记，我们 血浆中孤立的神经衍生的外泌体（NDE），发现这些外泌体高度富集 与大脑中表达的miRNA。在初步研究中，我们还发现 成人和青少年自杀人群中的大脑和NDE miRNA变化。许多miRNA的差异 在具有SI或SA的成年人和青少年中很常见；但是，一组独特的miRNA是相关的 独家自杀。此外，不同表达的NDE miRNA在 接受氯胺酮治疗的成年人。因此，我们的新颖方法为检测NDE miRNA提供了独特的机会 血浆，可用作自杀和治疗反应的生物标志物。根据我们的试点数据，我们 提案一个总体假设，即在青少年中，NDE miRNA的子集将有所不同 与具有MDD和健康对照的非自杀青少年相比，使用MDD和SI或SA。将有 与MDD，SI和SA有关的miRNA的独特子集。这些miRNA将具有特定的mRNA 可能与SI，SA和MDD风险相关的目标和生物途径。要测试这些，我们将检查 NDE miRNA和mRNA在以下青少年受试者组中的全基因组表达（11-19 y； n = 240）：1）MDD具有严重的SI和最近的SA（MDD+SA），2）MDD+SI，没有最近的SA，3）MDD没有MDD 最近的SI或SA（MDD-SI/SA）和4）没有精神障碍史的健康控制。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。这样，我们将 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 miRNA/mRNA调节途径与Si，SA和MDD有关，3）对AD治疗影响的反应 与MDD和SI/SA相关的NDE miRNA的差异。在240中使用现有的NDE miRNA数据集 在本研究提议的同一组中，成年人年龄在20-65岁之间，我们还将检查miRNA生物签名是否存在 对于青少年和成年人的MDD和SI/SA组很常见，或者如果年龄有所不同。总共，我们的研究 将提供新颖的途径，以将miRNA识别为开发生物标志物的``分子工具'' 跨年龄段的自杀性，最终是基于分子的新疗法，以治疗或预防这种疾病。