The Role of miR-132 in Neurodevelopmental Aspects of Schizophrenia

项目摘要 本提案中描述的实验目标是：1）表征microRNA（miRNA） 调节失调在精神分裂症中的作用是一种了解精神分裂症生物学基础的手段。 2）操纵不同发育阶段的miRNA水平，以便更好地了解 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结合。这种疾病与 严重的残疾和死亡率升高，并且在美国代表了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，其遗传学和病理生理学特征是： 人们对疾病的认识不足，导致治疗选择不足。 精神分裂症被认为是由参与神经发育的基因网络的扰动引起的， 神经可塑性大量基因的共同调节机制之一是通过microRNA （miRNA）调节编码RNA的稳定性和翻译。在进化过程中， 保守的蛋白质编码靶点，单个microRNA的失调可以产生广泛的影响 对基因表达和信号通路活性的影响。最近，几项研究已经确定了失调 人类精神分裂症脑组织或精神分裂症小鼠模型中的miRNA表达。 我们分析了800多个miRNAs在对照组和精神分裂症患者前额叶皮层组织中的表达， 研究人员发现了一个miR-132，它在精神分裂症中显著下调。 我们还证实了miR-132的表达在单独的精神分裂症人群中显著降低， 提示miR-132失调可能是该疾病的常见表型。在这项研究计划中， 我们将使用以下方法鉴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： 生物信息学和体外细胞生物学的结合。我们将描述精神分裂症的变化- 在出生后早期，前额叶皮层中miR-132功能受到抑制后的类似行为。 最后，我们将在多个发育阶段操纵miR-132的功能，并描述其对 行为、神经形态学和神经元功能。这些实验的结果将有助于 这不仅有助于我们理解miR-132在调节行为和神经功能中的作用， 我们对在不同的神经发育过程中破坏精神分裂症危险因素的影响的理解 阶段

PROJECT SUMMARY 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.