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是影响全球数百万人的最严重和最衰弱的疾病之一。尽管在过去的几十年中取得了相当大的进展，但仍然缺乏对MDD病因学的明确理解。越来越多的证据表明，抑郁症可能是由细胞级联损伤引起的，这导致调节情绪、认知和神经植物功能的回路中的异常信息处理。近年来，microRNAs（miRNAs）作为一类重要的非编码小分子RNA，通过与mRNA的3' UTR结合，抑制特定mRNA靶点的翻译和稳定性。由于miRNAs表现出高度调节的表达，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，一组miRNAs的表达在抑郁症患者的PFC中发生了改变，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miRNAs参与了神经可塑性。这些研究表明miRNAs可能在MDD的发病机制中起重要作用。我们假设，以协调方式调节的miRNA及其变体的子集将在MDD脑中显示差异共表达，其通过影响特定的神经/突触mRNA靶点和细胞通路，将参与MDD发病机制。在MDD和对照组的死后脑组织样本中，我们提出：1）通过小RNA测序分析miRNA表达，鉴定新的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鉴定mRNA和miRNA之间的调控关系; 3）分析miRNA-mRNA对，实验验证改变的miRNAs和特异性靶基因，并将这些改变定位于细胞水平; 4）分析MDD中差异共表达模块相关的通路; 5）通过确定pri-miRNA/pre-miRNA、RISC复合物和生物发生机制的组分来检查miRNA生物发生;和6）通过在突触体中经由小RNA测序确定miRNA富集来检查突触miRNA在MDD发病机制中的作用，分析在突触部分中特异性改变的miRNA-mRNA的靶基因和共表达模块，并在突触水平上检查pri-/pre-miRNA和miRNA生物发生机制的组分。通过使用最先进的高通量小RNA和RNA测序的组合，通过新的生物信息学工具和验证分析数据，识别特定细胞类型中miRNA及其靶点的变化，并检查miRNA在涉及情绪和认知的脑区突触水平上的作用，我们提出的研究在分子水平上推进MDD研究领域具有独特的地位。这些研究将为miRNAs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的疾病。