Role of noncoding RNAs in schizophrenia

描述(由申请人提供)：这是一项新的RO1拨款申请，旨在更好地了解非编码RNA调控网络在精神分裂症中与NMDA受体(NMDA-R)功能低下假说有关的作用。这一应用的基本假设是，特定的miRNAs或miRNAs家族在调节小鼠的精神分裂症样行为缺陷方面发挥了作用。这项提议的目标有三个：第一，我们将研究脑特定microRNAs(MiRNAs)在NMDA-R相关精神分裂症动物模型中的表达模式。具体地说，我们将在小鼠中检测急性或长期暴露于非竞争性NMDA-R拮抗剂和拟分裂药MK-801对人类患者与精神分裂症有关的大脑区域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表达异常的不同模式相关。重要的是，精神分裂症的药理学和遗传学模型之间的融合数据将为特定的miRNAs或miRNAs家族参与精神分裂症相关缺陷提供融合支持。重要的是，我们将检查已知对精神分裂症相关行为缺陷有有益影响的药物(氟哌啶醇和氯氮平)对拟分裂小鼠模型中失调的miRNAs表达的影响。据预测，已知临床用途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。为了更直接地评估已识别的miRNAs在小鼠精神分裂症样行为缺陷中的作用，我们将通过将锁定核酸(LNA)修饰的antagomir直接注入小鼠大脑来调节靶向miRNAs的表达。以这种方式调节靶向miRNAs的效果将在基线和MK-801诱导的行为中进行评估，这三个过程将模拟小鼠分裂样缺陷的各个方面：具有刻板印象的行为的多动；社交互动的减少；以及颅内自我刺激阈值的升高。据预测，miRNAs介导了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。本申请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/或生物标记物方法。与公共健康相关：精神分裂症是一种慢性精神疾病，其特征是对现实的感知或表达障碍，严重的社会或职业功能障碍，以及严重的认知障碍。因此，精神分裂症会给人类带来巨大的痛苦，给社会带来负面的经济影响。美国约1%的人口，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不清楚，显然需要改进治疗范例。这项拟议的工作有可能有助于开发全新的疗法。

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.