MicroRNA-mediated mechanisms of heroin drug seeking

MicroRNA介导的海洛因毒品寻找机制

• 批准号: 9764308
• 负责人: STEPHANIE Sillivan
• 金额: $ 24.4万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764308
• 关键词: Abstinence; Address; Alcohol or Other Drugs use; Alcohols; Amygdaloid structure; Animal Model; Animals; Behavior; Behavioral; Brain; Brain region; Cocaine; Complex; DNA Methylation; Data; Data Set; Disease model; Drug usage; Epidemiological trend; Fright; Funding; Future; Genes; Genetic Transcription; Genomics; Goals; Gold; Grant; Heroin; Human; Incidence; Individual; Knowledge; Learning; Maintenance; Mass Spectrum Analysis; Measures; Mechanics; Mediating; Mediation; Memory; Mentors; Methodology; MicroRNAs; Modeling; Modification; Molecular; Motivation; Mus; Opioid; Opioid agonist; Outcome; Overdose; Pathway interactions; Peptide Sequence Determination; Pharmaceutical Preparations; Pharmacology; Phase; Post-Traumatic Stress Disorders; Pre-Clinical Model; Process; Proteins; Proteome; Proteomics; Protocols documentation; Regulation; Rehabilitation therapy; Relapse; Research; Rodent Model; Role; Self Administration; Set protein; Small RNA; Solid; Stress; Testing; Tissues; Training; Withdrawal; Work; addiction; behavioral study; bioinformatics tool; cost; craving; drug craving; drug relapse; drug seeking behavior; druggable target; effective therapy; experience; experimental study; flexibility; frontal lobe; in vivo; insight; methylation pattern; miRNA expression profiling; mouse model; new therapeutic target; novel; opioid use; opioid withdrawal; prevent; programs; public health relevance; skills; substance use prevention; transcriptome sequencing

 DESCRIPTION (provided by applicant): Epidemiological trends indicate that the incidence of abuse and overdose of the highly addictive opioid heroin have more than tripled in recent years. However, effective treatment options are lacking and this is reflected in the high rates of opioid relapse and overdose. At the center of this issue lies the ability of drug cravings to persist and even strengthen long after opioid detoxification. The behavioral mechanics of this "incubation of craving" effect have become well-characterized in recent years, but more molecular insight is required to identify druggable targets within the brain that sustain drug seeking after prolonged abstinence. To that end, the goal of this project is to identify mechanisms that sustain strong drug seeking, guided by the hypothesis that microRNA (miRNA)-mediated translational mechanisms contribute to continued heroin seeking after prolonged abstinence. While their role in opioid seeking has not been described, miRNAs are an ideal focus for this study because each miRNA can target hundreds of genes, giving a single miRNA a high degree of mechanistic flexibility and a wide genomic range, capable of orchestrating complex behaviors. Indeed, limited exploration into their role in addiction has yielded exciting and promising results, such a regulation by opioid agonists and modification of alcohol and cocaine seeking. To address the goal of the project, the mentored phase of the grant will be used to gain training in heroin self-administration, protein sequencing and bioinformatic tools to identify miRNA-protein target interactions. At present, the candidate is studying the role of miRNAs in traumatic memory storage in a mouse model of post-traumatic stress disorder (PTSD) and in preliminary data employed small RNA sequencing (miRNA-Seq) to measure lasting miRNA expression (>30 days) after a traumatic learning experience. During the mentored K99 period, the scope of the current project will be extended to perform proteomic analysis and align it with the existing miRNA-Seq dataset, enabling the identification of miRNA pathways that will be functionally tested for their support of traumatic stress memories in the PTSD model. In the R00 period, the candidate will then apply the acquired skills and knowledge of miRNAs and opioid pharmacology to study miRNA mechanisms in the incubation of heroin craving using a rodent model of heroin self-administration. Focusing on two brain regions involved in the incubation of opioid craving, the central amygdala and orbitofrontal cortex, expression of miRNAs and their pathways will be manipulated in vivo to functionally identify miRNA mechanisms that sustain drug seeking after 30 days of abstinence from heroin. Completion of this project will identify new mechanisms of opioid seeking in the drug- free brain, which represents a critical step towards preventing substance use relapse.

 描述（由适用提供）：流行病学趋势表明，近年来，高度添加剂的阿片类药物海洛因的滥用和过量服用的事件已多三倍。但是，缺乏有效的治疗选择，这反映在阿片类药物救济和过量的高率中。这个问题的中心是毒品渴望在阿片类药物排毒后很长时间持续甚至增强的能力。近年来，这种“渴望孵化”效应的行为力学已变得充分表现，但是需要更多的分子洞察力来识别大脑中可吸毒的靶标，这些靶标在长期节制后维持药物寻求药物。为此，该项目的目的是确定在MicroRNA（miRNA）介导的翻译机制的指导下，确定寻求强大药物寻求药物的机制，这有助于延长节制后继续寻求海洛因。尽管尚未描述它们在Ooid寻求方面的作用，但miRNA是这项研究的理想重点，因为每个miRNA都可以靶向数百个基因，从而使单个miRNA具有高度的机械灵活性和广泛的基因组范围，能够协调复杂的行为。实际上，对成瘾作用的探索有限，产生了令人兴奋和有希望的结果，这种调节是对酒精和可卡因寻求的修改。为了解决该项目的目标，该赠款的修订阶段将用于获得海洛因自我给药，蛋白质测序和生物信息学工具的培训，以识别miRNA蛋白质靶标相互作用。目前，该候选人正在研究miRNA在创伤后应激障碍（PTSD）中的创伤记忆存储中的作用，以及在创伤性学习经历后使用的小RNA测序（miRNA-SEQ）在使用小的RNA测序（miRNA-SEQ）中测量持久miRNA表达（> 30天）。在物质K99期间，将扩展当前项目的范围以执行蛋白质组学分析并与现有的miRNA-Seq数据集保持一致，从而可以鉴定miRNA途径，该识别将在功能上测试，以支持他们在PTSD模型中对创伤性应力记忆的支持。在R00期间，候选人将使用miRNA和阿片类药理学的获得的技能和知识来研究miRNA机制，以使用海洛因自我管理模型孵化海洛因的渴望。专注于涉及阿片类药物渴望孵育的两个大脑区域，中央杏仁核和轨道额皮层，miRNA及其途径的表达将在体内操纵，以在功能上识别MiRNA机制，这些机制可维持在30天的戒酒中依赖海洛因30天后寻求药物的机制。该项目的完成将确定无毒大脑中阿片类药物寻求的新机制，这代表了防止药物消除的关键一步。