The Role of miR-132 in Neurodevelopmental Aspects of Schizophrenia

描述（由申请人提供）：本提案中描述的实验的目的是：1）表征microRNA（miRNA）失调在精神分裂症中的作用，作为深入了解该疾病生物学基础的一种手段; 2）操纵不同发育阶段的miRNA水平，以更好地了解精神分裂症的神经发育方面。精神分裂症是一种慢性精神疾病，影响全球约1%的人口，其特征是情感和认知症状的组合。这种疾病与严重的残疾和死亡率升高有关，在美国是一个巨大的医疗保健负担。虽然精神分裂症是最易遗传的精神疾病之一，但对该疾病的遗传学和病理生理学了解甚少，导致治疗选择不足。精神分裂症被认为是由参与神经发育和神经可塑性的基因网络的扰动引起的。大量基因可以被共调节的一种机制是通过microRNA（miRNA）调节编码RNA的稳定性和翻译。每个miRNA平均有300个进化上保守的蛋白质编码靶点，单个microRNA的失调可以对基因表达和信号通路活性产生广泛的影响。最近，一些研究已经确定了人类精神分裂症脑组织或精神分裂症小鼠模型中miRNA表达的失调。我们分析了对照组和精神分裂症患者前额叶皮质组织中超过800种miRNA的表达，并鉴定了一种似乎在精神分裂症中显着下调的miR-132。我们还证实，miR-132的表达显着减少，在一个单独的精神分裂症的人口，这表明，miR-132失调可能是一种常见的表型的疾病。在这项研究中，我们将使用生物信息学和体外细胞生物学相结合的方法，确定与精神分裂症有直接生物学相关性的miR-132蛋白编码靶点。然后，我们将描述出生后早期前额叶皮层中miR-132功能抑制后精神分裂症样行为的变化。最后，我们将在多个发育阶段操纵miR-132功能，并描述其对成年人行为、神经形态和神经功能的影响。这些实验的结果将有助于我们理解miR-132在调节行为和神经元功能中的作用，以及我们理解在不同神经发育阶段破坏精神分裂症风险因素的影响。 公共卫生相关性：精神分裂症是一种精神疾病，在美国影响着大约240万人，但由于对精神分裂症的生物学原因知之甚少，缺乏有效的治疗方法。一次调节大量基因的机制之一是通过一种称为microRNA（miRNA）的非编码RNA：改变单个miRNA的表达可以影响数百个蛋白质编码基因的表达。在这项资助中，我们将寻求了解miR-132在与精神分裂症相关的行为异常和神经病理学中的作用，目的是深入了解精神分裂症的生物学基础，并为未来的药物治疗确定新的靶点。

DESCRIPTION (provided by applicant): The goals of the experiments described in this proposal are to: 1) characterize the role that microRNA (miRNA) dysregulation plays in schizophrenia as a means to gaining insight into the biological underpinnings of the disorder; and 2) to manipulate miRNA levels at different stages of development in order to better understand the neurodevelopmental aspects of schizophrenia. Schizophrenia is a chronic psychiatric disorder that affects approximately 1% of the population worldwide and is characterized by a combination of affective and cognitive symptoms. The disorder is associated with significant disability and elevated mortality, and represents a large health care burden in the US. Although schizophrenia is among the most heritable of psychiatric disorders, the genetics and pathophysiology of the disorder are poorly understood, resulting in inadequate treatment options. Schizophrenia is believed to be caused by perturbations of gene networks involved in neurodevelopment and neuroplasticity. One mechanism by which large numbers of genes can be co-regulated is through microRNA (miRNA) regulation of coding RNA stability and translation. MiRNAs have an average of 300 evolutionarily conserved protein-coding targets each, and dysregulation of a single microRNA can have widespread effects on both gene expression and signaling pathway activity. Recently, several studies have identified dysregulation of miRNA expression in human schizophrenic brain tissue or mouse models of schizophrenia. We analyzed the expression of over 800 miRNAs in prefrontal cortical tissue from control and schizophrenic patients and identified a single miR, miR-132, that appears to be significantly downregulated in schizophrenia. We also confirmed that miR-132 expression is significantly reduced in a separate schizophrenic population, suggesting that miR-132 dysregulation may be a common phenotype of the disorder. In this research proposal, we will identify the miR-132 protein-coding targets that have direct biological relevancy to schizophrenia using a combination of bioinformatics and in vitro cell biology. We will then characterize changes in schizophrenia- like behaviors following inhibition of miR-132 function in the prefrontal cortex during the early postnatal period. Finally, we will manipulate miR-132 function at multiple developmental stages and characterize the effects on behavior, neuromorphology, and neuronal function in the adult. The results of these experiments will contribute both to our understanding of the role that miR-132 plays in regulating behavior and neuronal function, and to our understanding of the effects of disrupting a schizophrenia risk factor during different neurodevelopmental stages. PUBLIC HEALTH RELEVANCE: Schizophrenia is a psychiatric illness that affects approximately 2.4 million people in the US, but because the biological causes of schizophrenia are poorly understood, effective treatments are lacking. One mechanism of regulating a large number of genes at once is through a type of non-coding RNA known as microRNA (miRNA): changing the expression of a single miRNA can affect the expression of hundreds of protein-coding genes. In this grant, we will seek to understand the role that miR-132 plays in the behavioral abnormalities and neuropathology associated with schizophrenia with the goal of providing insight into the biological underpinnings of schizophrenia and identifying novel targets for future drug therapies.