Role of noncoding RNAs in schizophrenia

描述（由申请人提供）：这是一项新的RO1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。这一应用的潜在假设是，特定的mirna或mirna家族在调节小鼠精神分裂症样行为缺陷中发挥作用。本研究的目标有三个：首先，我们将研究NMDA-R相关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拮抗剂和拟分裂剂MK-801对人类精神分裂症患者大脑区域miRNA表达的影响，重点是前额叶皮质（PFC）。据预测，小鼠精神分裂症的药理学和遗传学模型将与miRNA表达失调的不同模式相关。重要的是，精神分裂症药理学和遗传学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有有益作用的药物（氟哌啶醇和氯氮平）对在拟分裂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地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，我们将通过将锁定的核酸（LNA）修饰的安塔戈米直接注入小鼠脑内来调节靶向mirna的表达。以这种方式调节靶向mirna对基线和mk -801诱导行为的影响将在三个程序中进行评估，这些程序模拟小鼠精神分裂症样缺陷的方面：过度运动与刻板行为；社会交往减少；颅内自我刺激阈值升高。预测miRNAs介导小鼠精神分裂症样缺陷的表达，降低靶向miRNAs的表达可能会减弱精神分裂症样缺陷的表达。本应用程序中提出的实验有望对精神分裂症的病理生理学产生重要的新见解，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。与公共卫生相关：精神分裂症是一种慢性精神障碍，其特征是感知或表达现实障碍，严重的社会或职业功能障碍以及严重的认知障碍。因此，精神分裂症给人类带来了巨大的痛苦，并对社会造成了负面的经济影响。美国大约1%的人口，大约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，并且明显需要改进治疗模式。这项建议的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.