microRNA dysregulation in psychiatric disorders and cognitive dysfunction

精神疾病和认知功能障碍中的 microRNA 失调

基本信息

批准号：
8490448
负责人：
JOSEPH A GOGOS
金额：
$ 38.15万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-15 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8490448
关键词：
22q11.2 A Mouse Accounting Adolescence Animals Applications Grants Architecture Attention Behavioral Binding Biological Brain Child Code Cognition Cognition Disorders Cognitive Complex Disease Down-Regulation Exhibits Functional RNA Functional disorder Gene Dosage Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Heterogeneity Genome Genomics Goals Hippocampus (Brain)Human Impaired cognition Individual Lesion Link Measures Mediating Mental disorders Messenger RNA MicroRNAs Modeling Molecular Molecular Profiling Molecular Target Mouse Strains Mus Mutation Nature Neurobiology Neurodevelopmental Disorder Neurons Nucleotides Pathway interactions Pattern Phenotype Physiological Processes Precursor RNA Prefrontal Cortex Process Proteins Regulation Repression Research Schizoaffective Disorders Schizophrenia Series Short-Term Memory Staging Synapses Synaptic Transmission Time Transcript Translations Variant Work behavioral impairment cognitive function emerging adult executive function gene interaction genetic risk factor human disease improved in vivo insight mRNA Transcript Degradation microdeletion mouse model neurobiological mechanism neurodevelopment neuron development new therapeutic target novel strategies prototype research study synaptic function

项目摘要

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) are a class of small non-coding regulatory RNAs. Abnormalities in miRNA expression and miRNA-mediated gene regulation have been observed in a variety of human diseases, including psychiatric and neurodevelopmental disorders. In most cases, miRNAs appear to be components of both the genetic architecture of these complex phenotypes and integral parts of the biological pathways that mediate the effects of the primary genetic deficits and could serve as novel therapeutic targets. Some of the strongest evidence for a direct pathogenic link between psychiatric disorders, cognitive dysfunction and miRNAs is provided by studies on the mouse model of a well- established genetic risk factor, the 22q11.2 microdeletion (Df(16)A+/- mice). Analysis of this mouse model provided compelling evidence that the 22q11.2 microdeletion results in abnormal processing of brain miRNAs. Our recent work has identified two major components of the 22q11.2-associated miRNA dysregulation, as well as a major downstream target of the miRNA dysregulation. Despite substantial progress, the extent to which miRNA dysregulation contributes to the cellular, synaptic and behavioral phenotypes associated with the 22q11.2 microdeletion in vivo remains to be determined and additional key downstream targets remain to be identified. This is the focus of this grant proposal. Understanding how miRNA-dependent gene regulation disrupted by a structural mutation with unequivocal causal links to schizophrenia and cognitive dysfunction contributes to the emergence of the psychiatric and cognitive phenotypes associated with this genomic imbalance will provide important mechanistic insights and can guide analysis of miRNA contribution to other psychiatric, neurodevelopmental and cognitive disorders.

描述（由申请人提供）：MicroRNA（miRNA）是一类小的非编码调节RNA。在多种人类疾病中观察到 miRNA 表达和 miRNA 介导的基因调控异常，包括精神疾病和神经发育障碍。在大多数情况下，miRNA 似乎是这些复杂表型的遗传结构的组成部分，也是介导主要遗传缺陷影响的生物途径的组成部分，并且可以作为新的治疗靶点。对已确定的遗传风险因素 22q11.2 微缺失（Df(16)A+/- 小鼠）的小鼠模型的研究提供了精神疾病、认知功能障碍和 miRNA 之间直接致病联系的最有力证据。。对该小鼠模型的分析提供了令人信服的证据，证明 22q11.2 微缺失会导致大脑 miRNA 的异常处理。我们最近的工作已经确定了 22q11.2 相关 miRNA 失调的两个主要组成部分，以及 miRNA 失调的主要下游靶点。尽管取得了实质性进展，但 miRNA 失调对体内 22q11.2 微缺失相关的细胞、突触和行为表型的影响程度仍有待确定，其他关键下游靶点仍有待确定。这是本次拨款提案的重点。了解 miRNA 依赖性基因调控如何被结构突变破坏，与精神分裂症和认知功能障碍有明确的因果关系，从而导致与这种基因组失衡相关的精神和认知表型的出现，这将提供重要的机制见解，并可以指导分析 miRNA 对其他疾病的贡献。精神、神经发育和认知障碍。