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The Role of miR-132 in Neurodevelopmental Aspects of Schizophrenia

miR-132 在精神分裂症神经发育方面的作用

基本信息

批准号：
8887138
负责人：
BROOKE H MILLER
金额：
$ 24.29万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8887138
关键词：
ARHGEF5 gene Adult Affect Affective Symptoms Animals Applications Grants Behavior Behavioral Bioinformatics Biological Brain CREB1 gene Cellular biology Chromosomal Rearrangement Chronic Code Development Disease Dopamine Down-Regulation Etiology Functional disorder Future Gene Expression Genes Genetic Goals Grant Healthcare Human Hyperactive behavior In Vitro Measures Mental disorders Mentors Messenger RNA MicroRNAs Molecular Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate NRG1 gene Neonatal Neurobehavioral Manifestations Neuronal Plasticity Neurons Nucleotides Patients Pharmacotherapy Phase Phenotype Physiologic pulse Play Population Prefrontal Cortex Proteins Puberty RNA Stability Regulation Research Proposals Risk Factors Role Schizophrenia Short-Term Memory Signal Pathway Signal Transduction Staging Synaptic plasticity Testing Tissue Model Tissues Translations Untranslated RNA Viral Vector Withdrawal brain tissue care burden design disability effective therapy genetic association genome wide association study in vitro Model in vivo in vivo Model insight mature animal mortality mouse model neurodevelopment neuron development neuropathology novel postnatal research study social vector

项目摘要

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.

项目总结本提案中描述的实验的目标是：1)表征microRNA(MiRNA)的作用调节失调在精神分裂症中发挥着作用，作为一种洞察精神分裂症的生物学基础的手段 2)在发育的不同阶段操纵miRNA水平，以便更好地理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，以情感和认知症状相结合为特征。这种疾病与严重的残疾和高死亡率，在美国是一个巨大的医疗负担。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人们对疾病知之甚少，导致治疗选择不足。精神分裂症被认为是由涉及神经发育和基因网络的基因网络扰动引起的神经可塑性。大量基因可以被共同调控的一种机制是通过microRNA (MiRNA)编码RNA稳定性和翻译的调节。在进化过程中，miRNAs平均有300个每一个保守的蛋白质编码靶标和单个microRNA的失调都可能产生广泛的影响对基因表达和信号通路活性的影响。最近，几项研究发现了失调。在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质组织中的表达。并发现了一个单一的miR，miR-132，它似乎在精神分裂症中显著下调。我们还证实miR-132在单独的精神分裂症人群中的表达显著减少，提示miR-132基因异常可能是该病的常见表型。在这项研究提案中，我们将使用以下方法确定与精神分裂症有直接生物学相关性的miR-132蛋白编码靶点生物信息学和体外细胞生物学的结合。然后我们将描述精神分裂症的变化-- 在出生后早期，miR-132在前额叶皮质中的功能受到抑制后出现类似的行为。最后，我们将在多个发育阶段操纵miR-132的功能，并表征其对成人的行为、神经形态和神经元功能。这些实验的结果将有助于这既有助于我们了解miR-132在调节行为和神经元功能中所起的作用，也有助于我们我们对精神分裂症危险因素在不同神经发育阶段的影响的理解各阶段。