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是影响全球数百万个人的最严重和令人衰弱的疾病之一。尽管在过去的几十年中取得了长足的进步，但仍然缺乏对MDD病因的清晰了解。积累的证据表明，MDD可能是由细胞级联反应的损害引起的，这些级联级联反应会导致调节情绪，认知和神经循环功能的电路中的异常信息处理。最近，microRNA（miRNA）已成为一类重要的小型非编码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显示出高度调节的表达，因此它们在特定转录组的发展和维持中做出了贡献，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，在MDD受试者的PFC中，一组miRNA的表达发生了变化，并且它们参与应对压力的反应。另外，积累的证据表明miRNA参与神经可塑性。这些研究表明，miRNA可能对MDD的疗法发生有重大贡献。我们假设以协调的方式调节miRNA及其变体的子集将显示MDD脑的差异共表达，而MDD脑则通过影响特定的神经/突触mRNA靶标和细胞途径，将参与MDD发病机理。在从MDD和对照对象获得的良好表征的事后大脑样品中，我们建议：1）通过小的RNA测序谱图miRNA表达，鉴定新型miRNA，并分析差异表达的miRNA； 2）通过映射共表达网络模块，通过RNA测序谱图mRNA表达并鉴定mRNA和miRNA之间的调节关系； 3）分析miRNA-mRNA对，验证miRNA和特定靶基因实验，并将这些变化定位在细胞水平上； 4）分析与MDD中差异共表达模块相关的途径； 5）通过确定生物发生机制的PRI-/RISC复合物和成分来检查miRNA生物发生；和6）检查突触miRNA在MDD发病机理中的作用，通过通过突触体中的小RNA测序来确定miRNA富集，分析突触分数中特异性改变的miRNA-mRNA的靶基因和共表达模块，并检查PRII/PRI-MIRNAS和MiRNA生物学水平的Mirna Biogogenesosic Marchinersic Machaptic Marchinersic presticals prinaptic intaptics prinaptic raction。通过使用最先进的高吞吐量小RNA和RNA测序的组合，通过新型的生物信息学工具和验证分析数据，鉴定miRNA及其在特定细胞类型中的靶标的变化，并检查miRNA在大脑区域中涉及的脑部和认知均研究的MORNAS在大脑区域中的作用，我们的建议层面是摩尔的研究，这是在我们的建议级别上的层面，这些层面是在整个领域中提前的，该领域是在领域中提高了MOLS的领域。这些研究将为MiRNA作为“分子工具”的发展提供新的途径，并有可能产生新的基于分子的疗法来治疗这种毁灭性疾病。