Genetic Vulnerability to Drugs of Abuse

对滥用药物的遗传脆弱性

基本信息

批准号：
8635321
负责人：
KARI J BUCK
金额：
$ 28.35万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-08-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8635321
关键词：
1q23.2 9p24 Address Affect Agonist Alcohol withdrawal syndrome Amygdaloid structure Animal Model Anxiety Architecture Area Barbiturates Behavior Behavioral Benzodiazepines Biological Biological Markers Brain Brain region Candidate Disease Gene Cell Nucleus Chemicals Chromosomes Chromosomes, Human, Pair 1 Chromosomes, Human, Pair 4 Clinical Cocaine Code Complement component C4a Complex Consumption Data Decision Making Dependence Development Dopamine Drug Addiction Drug usage Environmental Risk Factor Ethanol Ethanol dependence Funding GIRK3 subunit, G protein-coupled inwardly-rectifying potassium channel GTP-Binding Proteins Gene Expression Gene Expression Profile Genes Genetic Genetic Models Genetic Predisposition to Disease Hand Health Homologous Gene Human Human Identifications Ibotenic Acid Knock-out Lesion Letters Manuscripts Maps Mental Depression Methods Modeling Molecular Mus Neurons Oxidopamine Pathology Pathway Analysis Pentobarbital Pharmaceutical Preparations Phenotype Physiological Population Positioning Attribute Potassium Channel Predisposition Procedures Process Proteins Quantitative Trait Loci Relapse Role Scientist Self Administration Serotonin Receptor 5-HT2C Site Structure System Tertiary Protein Structure Testing United States National Institutes of Health Ventral Tegmental Area Weight Withdrawal addiction barbituric acid salt base complement C2a drug of abuse drug withdrawal gamma-Aminobutyric Acid gene interaction innovation inward rectifier potassium channel meetings novel pre-clinical receptor response sedative therapeutic target trait translational study transmission process treatment strategy zolpidem

项目摘要

DESCRIPTION (provided by applicant): Abuse of prescribed and other sedative drugs (e.g., benzodiazepines, barbiturates and ethanol) is among the top five health problems in the U.S. and is one of the most highly heritable addictive disorders. A host of biological (genetic) and environmental factors interact throughout the addictive process to influence drug use/abuse. Physiological dependence and associated withdrawal episodes are thought to constitute a motivational force that perpetuates sedative drug use/abuse and contributes to relapse. In humans, the identification of genes that influence drug dependence and withdrawal has been limited. Thus, the use of preclinical (animal) models that closely approximate the clinical situation is essential to elucidate the gene networks involved. We used these methods to identify two genes involved in sedative withdrawal in mice. The human homologs are now being studied in human populations by NIH intramural and other scientists. Quantitative trait loci (QTLs) are chromosome sites containing genes that influence a complex trait such as predisposition to drug withdrawal and consumption. Previously, we identified QTLs on chromosomes 1 and 4 with a large effect on sedative withdrawal in mice. During the current funding period, we fine-mapped these QTLs to 0.44 and 1.8 Mb intervals (syntenic with human 1q23.2 and 9p24-p22.3) and identified genes that code for MPDZ (the multi-PDZ domain protein) and GIRK3 (G-protein activated inwardly rectifying potassium channel subunit) as quantitative trait genes for drug withdrawal. Analyses of GIRK3 and MPDZ genetic models suggest that GIRK3 and MPDZ may also affect other addiction relevant phenotypes including sedative and cocaine self-administration. A key hypothesis of this proposal is that GIRK3 and MPDZ affect withdrawal from and self-administration (consumption) of multiple drugs of abuse. A second hypothesis is that the molecular network(s) associated with GIRK3 and MPDZ effects on behavior may interact at a mechanistic level. The aims may be summarized: 1) To elucidate the roles of MPDZ and GIRK3 in drug withdrawal and self- administration using novel MPDZ and GIRK3 genetic models. 2) To elucidate brain regions involved in GIRK3 and MPDZ effects on behavior using chemical lesions as primary procedures. 3) To test the role of GABAB and 5-HT2C receptors in GIRK3 and/or MPDZ actions with central administration of selective agonist/antagonists to GIRK3 and MPDZ genetic models and wildtype littermates. 4) To elucidate the MPDZ and GIRK3 network signalosomes using weighted gene co-expression network analysis (WGCNA). Gene expression will be assessed using the Illumina array (e.g., beginning with the central nucleus of the amygdala) utilizing novel MPDZ and GIRK3 genetic models, using withdrawn and control mice. In addition to identifying differentially expressed genes, innovative de novo network construction will allow us to elucidate the underlying regulatory structure at a high level of integration. This can direct further mechanistic studies and elucidate the important network(s), within which many biomarkers and drugable targets may exist to direct translational studies.

描述（由申请人提供）：滥用处方药和其他镇静药物（例如苯二氮卓类药物、巴比妥类药物和乙醇）是美国排名前五的健康问题之一，也是遗传性最高的成瘾性疾病之一。许多生物（遗传）和环境因素在整个成瘾过程中相互作用，影响药物的使用/滥用。生理依赖性和相关的戒断事件被认为构成了持续使用/滥用镇静药物并导致复发的动力。在人类中，影响药物依赖和戒断的基因的鉴定仍然有限。因此，使用非常接近临床情况的临床前（动物）模型对于阐明所涉及的基因网络至关重要。我们使用这些方法来鉴定与小鼠镇静戒断有关的两个基因。美国国立卫生研究院内部和其他科学家目前正在人群中研究人类同源物。数量性状基因座 (QTL) 是包含影响复杂性状（例如戒毒和消费倾向）的基因的染色体位点。此前，我们鉴定了 1 号和 4 号染色体上的 QTL，对小鼠镇静戒断有很大影响。在当前资助期间，我们将这些 QTL 精细映射到 0.44 和 1.8 Mb 间隔（与人类 1q23.2 和 9p24-p22.3 同线性），并鉴定了编码 MPDZ（多 PDZ 结构域蛋白）和 GIRK3（ G蛋白激活内向整流钾通道亚基）作为药物戒断的数量性状基因。 GIRK3 和 MPDZ 遗传模型的分析表明，GIRK3 和 MPDZ 也可能影响其他成瘾相关表型，包括镇静剂和可卡因自我给药。该提案的一个关键假设是 GIRK3 和 MPDZ 影响多种滥用药物的戒断和自我给药（消费）。第二个假设是与 GIRK3 和 MPDZ 对行为的影响相关的分子网络可能在机械水平上相互作用。目的可概括为： 1) 使用新型 MPDZ 和 GIRK3 遗传模型阐明 MPDZ 和 GIRK3 在药物戒断和自我给药中的作用。 2) 以化学损伤为主要程序，阐明参与 GIRK3 和 MPDZ 对行为影响的大脑区域。 3)通过对GIRK3和MPDZ遗传模型和野生型同窝动物集中施用选择性激动剂/拮抗剂来测试GABAB和5-HT2C受体在GIRK3和/或MPDZ作用中的作用。 4) 使用加权基因共表达网络分析 (WGCNA) 阐明 MPDZ 和 GIRK3 网络信号体。将使用 Illumina 阵列（例如，从杏仁核中央核开始）利用新的 MPDZ 和 GIRK3 遗传模型，使用撤回和对照小鼠来评估基因表达。除了识别差异表达基因外，创新的从头网络构建将使我们能够在高整合水平上阐明潜在的调控结构。这可以指导进一步的机制研究并阐明重要的网络，其中可能存在许多生物标志物和可药物靶点来指导转化研究。