Role of noncoding RNAs in schizophrenia

描述（由申请人提供）：这是一项新的RO 1资助申请，旨在更好地了解与NMDA受体（NMDA-R）功能减退假说相关的非编码RNA调控网络在精神分裂症中的作用。本申请的基本假设是特定的miRNA或miRNA家族在调节小鼠的精神分裂症样行为缺陷中起作用。本研究的目的有三：首先，我们将研究NMDA-R相关的精神分裂症动物模型中脑特异性microRNAs（miRNAs）的表达模式。具体来说，我们将在小鼠中研究急性或慢性暴露于非竞争性NMDA-R拮抗剂和拟神经递质MK-801对人类患者精神分裂症相关脑区miRNA表达的影响，重点是前额叶皮层（PFC）。据预测，小鼠精神分裂症的药理学和遗传模型将与失调的miRNA表达的不同模式相关。重要的是，精神分裂症的药理学和遗传模型之间的趋同数据将为特定miRNA或miRNA家族参与精神分裂症相关缺陷提供趋同支持。重要的是，我们将研究已知对精神分裂症相关行为缺陷具有有益作用的药物（氟哌啶醇和氯氮平）对拟精神分裂症小鼠模型中显示失调的miRNA表达的影响。据预测，具有已知临床效用的抗精神病药物将至少部分逆转精神分裂症小鼠模型中miRNA表达的失调模式。为了更直接地评估所鉴定的miRNA在小鼠精神分裂症样行为缺陷中的作用，我们将通过将锁核酸（LNA）修饰的miRNA直接脑内输注到小鼠脑中来调节靶向miRNA的表达。以这种方式调节靶向miRNA的影响将在基线和MK-801诱导的行为中进行评估，这些行为在小鼠中模拟了精神分裂症样缺陷的三个方面：具有刻板行为的过度运动;社会互动减少;颅内自我刺激阈值升高。据预测，miRNA介导小鼠中精神分裂症样缺陷的表达，并且降低靶向miRNA的表达可以减弱精神分裂症样缺陷的表达。本申请中提出的实验有望产生对精神分裂症病理生理学的重要新见解，并可能揭示精神分裂症相关行为缺陷的新治疗和/或生物标志物方法。与公共卫生的关系：精神分裂症是一种慢性精神障碍，其特征是对现实的感知或表达受损，严重的社会或职业功能障碍以及严重的认知障碍。因此，精神分裂症导致巨大的人类痛苦和对社会的负面经济影响。美国约有1%的人口，即约300万人患有精神分裂症。重要的是，精神分裂症的潜在病因在很大程度上仍然是未知的，有一个显着的需要改进的治疗模式。这项工作有可能有助于开发全新的治疗方法。

DESCRIPTION (provided by applicant): This is a new RO1 grant application seeking to gain a better understanding of the role of noncoding RNA regulatory networks relating to the NMDA receptor (NMDA-R) hypofunction hypothesis in schizophrenia. The underlying hypothesis of this application is that specific miRNAs or families of miRNAs play a role in regulating schizophrenia-like behavioral deficits in mice. The goals of this proposal are threefold: First, we will investigate expression patterns of brain-specific microRNAs (miRNAs) in NMDA-R- related animal models of schizophrenia. Specifically, we will examine in mice the effects of acute or chronic exposure to the non-competitive NMDA-R antagonist and schizomimetic agent, MK-801, on miRNA expression in brain regions implicated in schizophrenia in human patients, with a focus on prefrontal cortex (PFC). It is predicted that pharmacological and genetic models of schizophrenia in mice will be associated with distinct patterns of dysregulated miRNA expression. Importantly, convergent data between pharmacological and genetic models of schizophrenia will provide convergent support for the participation of particular miRNAs or families of miRNAs in schizophrenia-related deficits. Importantly, we will examine the effects of agents with known beneficial effects on schizophrenia-associated behavioral deficits (haloperidol and clozapine) on the expression of miRNAs shown to be dysregulated in the schizomimetic mouse models. It is predicted that antipsychotic agents with known clinical utility will reverse, at least in part, dysregulated patterns of miRNA expression in the mouse models of schizophrenia. To more directly assess the roles of identified miRNAs in schizophrenia-like behavioral deficits in mice, we will modulate the expression of targeted miRNAs by direct intracerebral infusion of locked nucleic acid (LNA)-modified antagomiRs into the brains of mice. The effects of modulating targeted miRNAs in this manner will be assessed on baseline and MK-801-induced behaviors in three procedures that model aspects of schizophrenia-like deficits in mice: hyperlocomotion with stereotyped behaviors; decreases in social interaction; and elevations of intracranial self-stimulation thresholds. It is predicted that miRNAs mediate the expression of schizophrenia-like deficits in mice and that decreasing the expression of targeted miRNAs may attenuate the expression of schizophrenia-like deficits. The experiments proposed in this application promise to yield significant new insights into the pathophysiology of schizophrenia, and may reveal novel treatment and/or biomarker approaches for schizophrenia-associated behavioral deficits. RELEVANCE TO PUBLIC HEALTH: Schizophrenia is a chronic psychiatric disorder characterized by impairments in perception or expression of reality, by significant social or occupational dysfunction and by profound cognitive impairment. Thus, schizophrenia results in tremendous human suffering and negative economic impact on society. Approximately 1% of the population of the United States, around 3 million people, suffers from schizophrenia. Importantly, the underlying etiology of schizophrenia remains largely unknown and there is a marked need for improved treatment paradigms. The proposed work has the potential to aid in the development of completely novel therapeutics.