Role of noncoding RNAs in schizophrenia

非编码 RNA 在精神分裂症中的作用

基本信息

批准号：
8037018
负责人：
Claes Robert Wahlestedt
金额：
$ 34.08万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8037018
关键词：
Accounting Acute Animal Model Antipsychotic Agents Antisense Oligonucleotides Applications Grants Attention Attenuated Autopsy Behavior Behavioral Bioinformatics Biological Assay Biological Markers Biological Models Brain Brain region Cells Chronic Clinical Clozapine Code Complement Complex Critical Pathways Data Development Disease Etiology Exposure to Family Functional disorder Genetic Genetic Models Glutamates Goals Haloperidol Health Health Expenditures Human Impaired cognition Impairment In Situ Hybridization In Vitro Infusion procedures Luciferases Mediating Mental disorders Messenger RNA MicroRNAs Modeling Molecular Mus N-Methyl-D-Aspartate Receptors NMDA receptor antagonist NR1 gene Neurons Occupational Pathology Patients Pattern Perception Physiological Play Population Prefrontal Cortex Procedures Proteins RNA Regulation Relative (related person)Reporter Risk Role Schizophrenia Self Stimulation Single Nucleotide Polymorphism Social Interaction Societies Stereotyped Behavior Susceptibility Gene Synapses Synaptic plasticity System Transcript Transgenic Mice United States Untranslated RNA Validation Western Blotting Work economic impact human tissue improved in vitro Model in vivo insight interest locked nucleic acid mouse model novel novel therapeutics research study social transcriptomics transmission process

项目摘要

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.

描述（由申请人提供）：这是一种新的RO1赠款应用程序，旨在更好地了解与NMDA受体（NMDA-R）功能低下的非编码RNA调节网络在精神分裂症中的作用。该应用的基本假设是，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。该提案的目标是三重：首先，我们将研究精神分裂症的NMDA-R-相关动物模型中脑特异性microRNA（miRNA）的表达模式。具体而言，我们将在小鼠中检查急性或慢性暴露于非竞争力NMDA-R拮抗剂和精神分裂剂MK-801，对人类患者中与精神分裂症的大脑区域中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和遗传模型将与miRNA表达失调的不同模式有关。重要的是，精神分裂症的药理学和遗传模型之间的收敛数据将为特定的miRNA或miRNA家族在精神分裂症相关的缺陷中的参与提供收敛支持。重要的是，我们将研究具有已知有益作用的药物对精神分裂症相关的行为缺陷（氟哌啶醇和氯氮平）对在精神分裂小鼠模型中显示失调的miRNA表达的影响。据预测，具有已知临床实用性的抗精神病药将至少部分地反转，在精神分裂症小鼠模型中，miRNA表达的模式失调。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，我们将通过直接脑内输注锁定的核酸（LNA）转化为小鼠脑中的锁骨核酸（LNA）转化的反瘤来调节靶向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，以模拟小鼠中精神分裂症样缺陷的各个方面：具有刻板印象的超置换性；社会互动的减少；和颅内自刺激阈值的升高。据预测，miRNA介导小鼠精神分裂症样缺陷的表达，并且降低靶向miRNA的表达可能会减弱精神分裂症样缺陷的表达。在此应用程序中提出的实验有望对精神分裂症的病理生理产生重大的新见解，并可能揭示了与精神分裂症相关的行为缺陷的新型治疗和/或生物标志物方法。与公共卫生的相关性：精神分裂症是一种慢性精神疾病，其特征是现实感知或表达的障碍，严重的社会或职业功能障碍以及严重的认知障碍。因此，精神分裂症会导致巨大的人类苦难和对社会的负面影响。大约1％的美国人口（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仍然在很大程度上未知，并且明显需要改善治疗范例。拟议的工作有可能帮助发展完全新颖的治疗疗法。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Landscape of long noncoding RNA classification.

DOI：
10.1016/j.tig.2015.03.007
发表时间：
2015-05
期刊：
TRENDS IN GENETICS
影响因子：
11.4
作者：
St Laurent, Georges;Wahlestedt, Claes;Kapranov, Philipp
通讯作者：
Kapranov, Philipp

Regulation of the apolipoprotein gene cluster by a long noncoding RNA.

DOI：
10.1016/j.celrep.2013.12.015
发表时间：
2014-01-16
期刊：
Cell reports
影响因子：
8.8
作者：
Halley P;Kadakkuzha BM;Faghihi MA;Magistri M;Zeier Z;Khorkova O;Coito C;Hsiao J;Lawrence M;Wahlestedt C
通讯作者：
Wahlestedt C

MicroRNA dysregulation in psychiatric disease.