Genetic Vulnerability to Drugs of Abuse

滥用药物的遗传脆弱性

基本信息

批准号：
8187522
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/8187522
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. PUBLIC HEALTH RELEVANCE: The proposed studies address genetic mechanisms involved in drug physiological dependence and associated withdrawal, and their broader role in addiction-relevant behaviors including self-administration. Elucidating the genetic bases of these mechanisms will provide a significant boost not only in understanding the underlying pathology but also in the development of new treatment strategies.

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，并且是最高度可行的上瘾疾病之一。在整个成瘾过程中，许多生物（遗传）和环境因素相互作用，以影响药物使用/滥用。人们认为生理依赖性和相关的戒断事件构成了一种动机，使镇静药物使用/滥用延续并有助于复发。在人类中，影响药物依赖性和戒断的基因的鉴定受到限制。因此，使用紧密近似临床情况的临床前（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识别小鼠镇静剂戒断的两个基因。 NIH壁内和其他科学家正在研究人类的人类同源物。定量性状基因座（QTL）是染色体位点，其中包含影响复杂性状的基因，例如药物戒断和消耗的易感性。以前，我们在染色体1和4上鉴定了QTL，对小鼠的镇静性戒断产生巨大影响。 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.对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的表型，包括镇静剂和可卡因自我管理。该提案的一个关键假设是Girk3和MPDZ会影响多种滥用药物的撤离和自我管理（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会在机械水平上相互作用。目的可以总结：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）阐明使用化学病变作为主要程序的GIRK3和MPDZ涉及行为的大脑区域。 3）测试GABAB和5-HT2C受体在GIRK3和/或MPDZ作用中的作用，并在中央给药选择性激动剂/拮抗剂对GIRK3和MPDZ遗传模型以及Wildtype乱货物中的作用。 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。将使用新型MPDZ和GIRK3遗传模型，使用撤回和对照小鼠，使用Illumina阵列（例如，从杏仁核的中央核开始）评估基因表达。除了鉴定差异表达的基因外，创新的从头网络构建还将使我们能够在高度集成下阐明潜在的监管结构。这可以指导进一步的机械研究并阐明重要的网络，其中许多生物标志物和可吸毒靶标可能会引导转化研究。公共卫生相关性：拟议的研究涉及与药物生理依赖性和相关戒断涉及的遗传机制，以及它们在与成瘾相关的行为（包括自我管理）中的更广泛作用。阐明这些机制的遗传基础将不仅为理解潜在的病理，而且在发展新治疗策略的发展方面提供了重大的推动。