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: 8287682
• 负责人: Paul J. Kenny
• 金额: $ 42.78万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287682
• 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; 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）：本申请响应 RFA-DA-08-016，旨在研究非编码 RNA 在神经可塑性和成瘾中的作用。具体来说，我们试图了解 microRNA (miRNA) 在强迫性寻药中的作用。 miRNA 是一个小（约 22 个核苷酸）非编码 RNA 家族，可以通过与目标 mRNA 转录物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。新的证据表明 miRNA 可能在神经可塑性中发挥重要作用，但它们在成瘾相关行为缺陷中的作用尚不清楚。具体目标 I 将涉及在强迫性可卡因消费动物模型中表征 miRNA 的大脑表达模式。具体来说，我们将检查大鼠每天限制（1 小时）或延长（6 小时）静脉注射可卡因自我给药的效果，这会导致每日可卡因摄入量强迫性地增加，对整个皮质中 miRNA 表达的影响皮质下大脑区域与毒瘾神经病理学密切相关。此外，我们还将评估人类可卡因成瘾者死后脑组织中相同大脑区域的 miRNA 表达模式。据预测，大鼠和人类的强迫性寻找可卡因将与不同的 miRNA 表达失调模式相关。重要的是，大鼠和人体组织之间的趋同数据将为特定 miRNA 或 miRNA 家族参与成瘾相关神经可塑性提供支持。在 Specific Aim II 中，我们将直接评估在强迫性寻找可卡因的大鼠中发生的 miRNA 表达模式改变的相关性。具体来说，我们将向离散的大脑区域注入慢病毒载体，以过表达或锁核酸 (LNA) 修饰的 antagomiR，以敲低靶向 miRNA。将评估以这种方式调节目标 miRNA 对大鼠强迫性可卡因寻找行为的影响。具体目标 III 将涉及 miRNA 的功能表征，这些 miRNA 可以调节强迫性可卡因寻找。在这里，将研究其表达调节可卡因寻找的 miRNA 的细胞定位、调节机制以及这些 miRNA 作用的潜在目标 mRNA 转录物的识别。拟议的工作有望对成瘾的病理生理学产生重要的新见解，并可能揭示针对这种破坏性疾病的新治疗和/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疾病给社会带来了巨大的健康负担。事实上，可卡因的使用与心律失常、心肌梗塞和脑出血等潜在致命的心血管事件有关，并导致约 5.8 亿美元的直接医疗费用。因此，添加可卡因给人类带来巨大痛苦并对社会造成负面经济影响。重要的是，驱动强迫性药物寻求的潜在病理生理学在很大程度上仍然未知，并且明显需要改进的治疗范例。拟议的工作有可能有助于开发全新的疗法。