Role of MicroRNAs in the Mechanisms of Drug Dependence

MicroRNA 在药物依赖性机制中的作用

• 批准号: 7687401
• 负责人: Paul J. Kenny
• 金额: $ 42.95万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687401
• 关键词: Abstinence; Animal Model; Antisense Oligonucleotides; Applications Grants; Arrhythmia; Attention; Automobile Driving; Behavior; Behavioral; Binding; Bioinformatics; Biological Assay; Biological Markers; Brain; Brain region; Cardiovascular system; Cerebral hemisphere hemorrhage; Clinical; Cocaine; Cocaine Dependence; Cocaine Users; Code; Commit; Complement; Complex; Consumption; Critical Pathways; Data; Development; Disease; Drug Addiction; Etiology; Event; Family; Functional RNA; Functional disorder; Gene Expression; Goals; Health; Health Care Costs; Human; In Situ Hybridization; In Vitro; Intake; Interdisciplinary Study; Intravenous; Investigation; Knowledge; Lentivirus Vector; Luciferases; Maintenance; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Profiling; Myocardial Infarction; Neurobiology; Neuronal Plasticity; Nucleotides; Pathology; Pattern; Pharmaceutical Preparations; Play; Productivity; Proteins; Public Health; RNA; Rattus; Records; Regulation; Relapse; Relative (related person); Reporter; Role; Scientist; Self Administration; Societies; Substance abuse problem; Synapses; Transcript; Translations; Untranslated RNA; Validation; Western Blotting; Work; addiction; brain tissue; cocaine use; economic impact; human subject; human tissue; improved; in vivo; insight; interest; knock-down; locked nucleic acid; neuropathology; novel; novel therapeutics; public health relevance; response; transcriptomics

DESCRIPTION (provided by applicant): This application in response to RFA-DA-08-016 is aimed at investigating the role of non-coding RNAs in neuroplasticity and addiction. Specifically, we seek to gain an understanding of the role of microRNAs (miRNAs) in compulsive drug seeking. miRNAs are a family of small (~22 nucleotides) noncoding RNAs that can regulate gene expression by binding to complementary sequences in target mRNA transcripts to facilitate their degradation and/or inhibit their translation. Emerging evidence suggests that miRNAs may play an important role in neuroplasticity, but their role in addiction-related behavioral deficits is unknown. Specific Aim I will involve characterization of brain expression patterns of miRNAs in an animal model of compulsive cocaine consumption. Specifically, we will examine the effects of restricted (1 h) or extended (6 h) daily access to intravenous cocaine self-administration in rats, which results in a compulsive-like escalation of daily cocaine intake, on the expression of miRNAs throughout cortical and subcortical brain regions heavily implicated in drug addiction neuropathology. In addition, we will also assess miRNA expression patterns in the same brain regions in post-mortem brain tissues from human cocaine addicts. It is predicted that compulsive cocaine seeking in rats and humans will be associated with distinct patterns of dysregulated miRNA expression. Importantly, convergent data between the rat and human tissues will provide support for the participation of particular miRNAs or families of miRNAs in addiction-related neuroplasticity. In Specific Aim II we will directly assess the relevance of the altered expression patterns of miRNAs that occur in rats compulsively seeking cocaine. Specifically, we will infuse into discrete brain regions lentiviral vectors to over-express, or locked nucleic acid (LNA)-modified antagomiRs to knock-down, targeted miRNAs. The effects of modulating targeted miRNAs in this manner will be assessed on compulsive cocaine seeking behavior in rats. Specific Aim III will involve functional characterization of miRNAs shown to modulate compulsive cocaine seeking. Here, miRNAs whose expression modulates cocaine seeking will be studied with respect to cellular localization, mechanism of regulation and identification of potential target mRNA transcripts upon which these miRNAs act. The proposed work promises to yield significant new insights into the pathophysiology of addiction, and may reveal novel treatment and/or biomarker approaches for this devastating disorder. PUBLIC HEALTH RELEVANCE: Substance abuse disorders including cocaine addiction are a tremendous health burden to society. Indeed, cocaine use is associated with potentially fatal cardiovascular events such as arrhythmias, myocardial infarction, and cerebral hemorrhage, and results in approximately $580 million in direct healthcare costs. Thus, cocaine addition results in tremendous human suffering and negative economic impact on society. Importantly, the underlying pathophysiology that drives compulsive drug seeking 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）：响应RFA-DA-08-016的申请旨在研究非编码RNA在神经塑性和成瘾中的作用。具体而言，我们试图了解microRNA（miRNA）在强迫性药物寻求药物中的作用。 miRNA是一个小（约22个核苷酸）非编码RNA的家族，可以通过与靶mRNA转录中的互补序列结合来调节基因表达，以促进其降解和/或抑制其翻译。新兴的证据表明，miRNA可能在神经塑性中起重要作用，但是它们在与成瘾相关的行为缺陷中的作用尚不清楚。具体目的我将涉及对可卡因消耗的动物模型中miRNA的脑表达模式的表征。具体而言，我们将研究受限制的（1 h）或延长（6 h）每日访问大鼠静脉吸气自我给药的影响，这会导致每日可卡因摄入的强迫性升级，对miRNA的表达，在整个皮质中的表达以及皮层脑区域与药物成瘾神经病理学有关。此外，我们还将评估人类可卡因成瘾者在尸体后脑组织中相同大脑区域中的miRNA表达模式。据预测，在大鼠和人类中寻求可卡因将与miRNA表达失调的不同模式有关。重要的是，大鼠和人体组织之间的收敛数据将为特定的miRNA或miRNA家族在与成瘾相关的神经塑性中的参与提供支持。在特定的目标II中，我们将直接评估强迫寻求可卡因的大鼠中发生的miRNA的改变表达模式的相关性。具体而言，我们将注入离散的大脑区域慢病毒载体过表达或锁定的核酸（LNA）修饰的antagomirs以敲除靶向的miRNA。以这种方式调节靶向miRNA的影响将对强迫性可卡因寻求大鼠的行为进行评估。特定的目标III将涉及显示的miRNA的功能表征，以调节强迫性可卡因寻求。在这里，将研究其表达调节可卡因寻求的miRNA有关细胞定位，调节机理和这些miRNA作用的潜在靶mRNA转录本的鉴定。拟议的工作有望对成瘾的病理生理产生重大的新见解，并可能揭示了这种毁灭性疾病的新颖治疗方法和/或生物标志物方法。 公共卫生相关性：包括可卡因成瘾在内的药物滥用障碍对社会带来了巨大的健康负担。确实，可卡因的使用与潜在的致命心血管事件有关，例如心律不齐，心肌梗塞和脑出血，并导致直接医疗费用约为5.8亿美元。因此，可卡因增加会导致巨大的人类苦难和对社会的负面影响。重要的是，驱动强迫性药物寻求药物的潜在病理生理学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。