microRNA dysregulation in psychiatric disorders and cognitive dysfunction

描述（由申请人提供）：MicroRNAs （miRNAs）是一类小的非编码调控rna。在包括精神和神经发育障碍在内的多种人类疾病中，已经观察到miRNA表达和miRNA介导的基因调控异常。在大多数情况下，mirna似乎既是这些复杂表型的遗传结构的组成部分，也是介导原发性遗传缺陷影响的生物学途径的组成部分，可以作为新的治疗靶点。精神疾病、认知功能障碍和miRNAs之间存在直接致病联系的一些最强有力的证据是通过对小鼠模型的研究提供的，该模型具有一种公认的遗传风险因素，即22q11.2微缺失（Df(16) a +/-小鼠）。对该小鼠模型的分析提供了令人信服的证据，表明22q11.2微缺失导致脑mirna的异常加工。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失调的一个主要下游靶点。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，其他关键的下游靶点仍有待确定。这是本拨款提案的重点。了解miRNA依赖的基因调控如何被与精神分裂症和认知功能障碍有明确因果关系的结构突变破坏，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，将提供重要的机制见解，并可以指导miRNA对其他精神、神经发育和认知障碍的分析。

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. PUBLIC HEALTH RELEVANCE: This proposal is inherently translational in nature, aimed at elucidating the neurobiological substrates of psychiatric disease. It is aimed at identifying specific patterns of abnormal gene expression caused by loci predisposing to schizophrenia and cognitive dysfunction and link them to the cellular, synaptic and cognitive processes they impact. Identifying such patterns would set the stage for a novel approach to therapies aimed at reversing the underlying pathophysiology and restoring normal function.