MicroRNA Mapping in Major Depression

重度抑郁症中的 MicroRNA 作图

• 批准号: 8647464
• 负责人: Yogesh Dwivedi
• 金额: $ 36.09万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-05 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647464
• 关键词: 3' Untranslated Regions; Affect; Antibodies; Area; Autopsy; Biogenesis; Bioinformatics; Biological Assay; Biological Preservation; Biological Process; Brain; Brain region; Cells; Characteristics; Cognition; Complex; Control Groups; Data; Dendrites; Depressed mood; Development; Diagnostic; Disease; Docking; Etiology; Functional RNA; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Polymorphism; Hippocampus (Brain); Impairment; In Situ Hybridization; In Vitro; Individual; Investigation; Lead; Luciferases; Maintenance; Major Depressive Disorder; Maps; Measures; Mental Depression; Messenger RNA; MicroRNAs; Molecular; Moods; Nature; Neural Pathways; Neuronal Plasticity; Pathogenesis; Pathology; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Physiological; Play; Positioning Attribute; Post-Transcriptional Regulation; Process; Proteins; RNA Binding; RNA Sequence Analysis; RNA Sequences; Regulation; Regulator Genes; Relative (related person); Research; Role; Sampling; Small RNA; Stress; Synapses; Synaptic plasticity; Synaptosomes; Testing; Therapeutic; Tissue-Specific Gene Expression; Translations; Validation; Variant; Weight; Western Blotting; base; case control; cell type; cellular targeting; cofactor; coping; disease phenotype; disorder control; genome-wide; human DICER1 protein; information processing; interest; mRNA Expression; novel; protein expression; public health relevance; relating to nervous system; response; statistics; therapeutic target; tool

DESCRIPTION (provided by applicant): MDD is one of the most severe and debilitating illnesses that affects millions of individuals worldwide. Despite considerable advances over the past decades, a clear understanding of the etiology of MDD is still lacking. Accumulating evidence suggests that MDD may arise from impairments in cellular cascades, which lead to aberrant information processing in the circuits that regulate mood, cognition, and neurovegetative functions. Recently, microRNAs (miRNAs) have emerged as an important class of small non-coding RNAs that by binding to 3' UTR of mRNAs, suppress the translation and/or stability of specific mRNA targets. Since miRNAs show a highly regulated expression, they contribute in the development and maintenance of a specific transcriptome and thus have the unique ability to influence physiological and disease phenotypes. Our recent studies show that the expression of a group of miRNAs is altered in PFC of MDD subjects and that they are involved in coping response to stress. In addition, accumulative evidence points to the involvement of miRNAs in neural plasticity. These studies suggest a strong possibility that miRNAs may contribute significantly to the etiopathogenesis of MDD. We hypothesize that subsets of miRNAs and their variants, regulated in a coordinated fashion, will show differential co-expression in MDD brain, which by affecting specific neural/synaptic mRNA targets and cellular pathways, will participate in MDD pathogenesis. In well characterized postmortem brain samples obtained from MDD and control subjects, we propose to: 1) profile miRNA expression by small RNA sequencing, identify novel miRNAs, and analyze differentially expressed miRNAs; 2) profile mRNA expression by RNA sequencing and identify regulatory relationships between mRNA and miRNA by mapping co-expression network modules; 3) analyze miRNA-mRNA pairs, validate altered miRNAs and specific target genes experimentally, and localize these changes at the cellular level; 4) analyze pathway associated with differentially co-expressed modules in MDD; 5) examine miRNA biogenesis by determining pri-/pre-miRNAs, RISC complexes, and components of biogenesis machinery; and 6) examine the role of synaptic miRNAs in MDD pathogenesis by determining miRNA enrichment via small RNA sequencing in synaptosomes, analyzing target genes and co-expression modules of miRNA-mRNA specifically altered in the synaptic fraction, and examining pri-/pre-miRNAs and components of miRNA biogenesis machinery at synaptic level. By using a combination of the state-of-the-art high throughput small RNA and RNA sequencing, analyzing data by novel bioinformatics tools and validation, identifying changes in miRNAs and their targets in specific cell type(s), and examining the role of miRNAs at the synaptic level in brain regions implicated in mood and cognition, our proposed study is uniquely positioned to advance the field of MDD research at the molecular level. These investigations will provide novel avenues for the development of miRNAs as ''molecular tools'' with the potential to generate new molecular-based therapies to treat this devastating disorder.

描述（由申请人提供）：MDD 是影响全世界数百万人的最严重、最使人衰弱的疾病之一。尽管过去几十年取得了长足的进步，但对 MDD 的病因学仍然缺乏清晰的认识。越来越多的证据表明，MDD 可能是由细胞级联损伤引起的，细胞级联损伤导致调节情绪、认知和神经植物功能的回路中信息处理异常。最近，microRNA (miRNA) 已成为一类重要的小非编码 RNA，通过与 mRNA 的 3' UTR 结合，抑制特定 mRNA 靶标的翻译和/或稳定性。由于 miRNA 显示出高度调控的表达，它们有助于特定转录组的发育和维持，因此具有影响生理和疾病表型的独特能力。我们最近的研究表明，MDD 受试者的 PFC 中一组 miRNA 的表达发生了改变，并且它们参与了对压力的应对反应。此外，越来越多的证据表明 miRNA 参与神经可塑性。这些研究表明 miRNA 很可能对 MDD 的发病机制发挥重要作用。我们假设以协调方式调节的 miRNA 子集及其变体将在 MDD 大脑中表现出差异性共表达，通过影响特定的神经/突触 mRNA 靶标和细胞通路，参与 MDD 发病机制。在从 MDD 和对照受试者获得的经过充分表征的死后大脑样本中，我们建议：1）通过小 RNA 测序分析 miRNA 表达，识别新的 miRNA，并分析差异表达的 miRNA； 2）通过RNA测序分析mRNA表达，并通过绘制共表达网络模块来识别mRNA和miRNA之间的调控关系； 3）分析miRNA-mRNA对，通过实验验证改变的miRNA和特定靶基因，并在细胞水平上定位这些变化； 4) 分析MDD中差异共表达模块相关的通路； 5) 通过确定 pri-/pre-miRNA、RISC 复合物和生物发生机制的组成部分来检查 miRNA 的生物发生； 6) 通过突触体中小 RNA 测序确定 miRNA 富集度，分析突触部分中特异性改变的 miRNA-mRNA 的靶基因和共表达模块，并检查 pri-/pre-miRNA，从而检查突触 miRNA 在 MDD 发病机制中的作用以及突触水平上 miRNA 生物发生机制的组成部分。通过结合使用最先进的高通量小 RNA 和 RNA 测序，通过新型生物信息学工具和验证分析数据，识别特定细胞类型中 miRNA 及其靶标的变化，并检查大脑区域突触水平的 miRNA 与情绪和认知有关，我们提出的研究具有独特的定位，可以在分子水平上推进 MDD 研究领域。这些研究将为 miRNA 作为“分子工具”的开发提供新的途径，并有可能产生新的基于分子的疗法来治疗这种破坏性疾病。