The Role of Mpdz in Ethanol Withdrawal and Genetically Correlated Behaviors

Mpdz 在乙醇戒断和遗传相关行为中的作用

• 批准号: 7826852
• 负责人: KARI J BUCK
• 金额: $ 34.3万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7826852
• 关键词: 9p24; Acute; Affect; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Alleles; Animal Model; Animals; Arts; Ataxia; Bacterial Artificial Chromosomes; Basal Ganglia; Behavior; Behavioral; Behavioral Model; Biological; Brain; Brain region; Budgets; Cells; Chromosomes; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 4; Chronic; Clinical; Complement; Complex; Congenic Strain; Convulsions; Data; Dependence; Environmental Risk Factor; Ethanol; Funding; Future; GABA Receptor; GTP Binding; Gene Proteins; Gene Transfer; Genes; Genetic; Genetic Models; Genetic Risk; Genome; Genotype; Goals; Human; Human Chromosomes; Human Identifications; Length; Lesion; Manuscripts; Maps; Mediating; Medical; Methods; Microinjections; Modeling; Mouse Strains; Mus; Pathway interactions; Physiological; Population; Predisposition; Process; Protein Isoforms; Proteins; Quantitative Trait Loci; RNA Interference; Regulation; Relapse; Research; Role; Scientist; Serotonin; Severities; Signal Transduction Pathway; Site; Staging; Substantia nigra structure; Synapses; Synaptic Transmission; Taste Perception; Tertiary Protein Structure; Testing; Transcript; Transgenic Animals; Transgenic Mice; Transgenic Model; Transgenic Organisms; United States; Viral; Withdrawal; Work; alcohol response; base; congenic; design; drinking; gamma-Aminobutyric Acid; in vivo; indexing; innovation; meetings; neural circuit; neurochemistry; neurophysiology; novel; pre-clinical; problem drinker; protein expression; protein function; receptor; receptor function; relating to nervous system; response; tool; trait; transcription factor; transmission process

DESCRIPTION (provided by applicant): Alcoholism and alcohol abuse are complicating factors in most chronic medical and psychiatric illnesses. Alcohol physiological dependence and associated withdrawal episodes are thought to constitute a powerful motivational force that perpetuates continued alcohol use/abuse and contributes to relapse. In humans, the identification of genes that influence alcohol physiological dependence and withdrawal has been extremely limited. Thus, the use of preclinical (animal) models of alcohol physiological dependence that closely approximate the clinical situation is essential to elucidate the gene networks involved. We have used these methods to identify a gene (Mpdz) involved in alcohol withdrawal in mice that is now being studied in populations of human alcoholics by NIH-NIAAA intramural scientists. Quantitative trait loci (QTLs) are chromosome sites containing alleles (genes) that influence a quantitative (complex) trait such as predisposition to alcohol physiological dependence and associated withdrawal. Previously, we confirmed QTLs on chromosomes (Chr) 1, 4, and 11 that jointly have a major influence on alcohol withdrawal in mice. This proposal is focused on the Chr 4 QTL with proven effects on acute and chronic ethanol withdrawal. During the current funding period, we fine mapped this QTL to a 1.8 Mb (<1 cM) interval (syntenic with human Chr 9p24-p22.3) and identified Mpdz (which encodes the multiple PDZ domain protein, MPDZ or MUPP1) as a quantitative trait gene (QTG) for alcohol withdrawal. Using a congenic strain that isolates this locus on an inbred genetic background as well as novel Mpdz transgenic animal models, we propose to continue toward elucidation of the mechanism by which Mpdz affects alcohol withdrawal. We propose the following three aims: (1) Using viral mediated gene transfer and/or RNA interference approaches, rigorously test the hypothesis that Mpdz expression in circuitry implicated in ethanol withdrawal in fact influences withdrawal severity. Pharmacological manipulation in discrete brain regions will provide mechanistic information about MPDZ and its influence on ethanol withdrawal. (2) Use neurochemical and neurophysiological analyses to provide mechanistic answers to identify a signal transduction pathway influenced by MPDZ. (3) Using congenic and Mpdz transgenic animal models, test Mpdz's role in behavioral responses to ethanol (i.e., acceptance drinking, conditioned taste aversion, ataxia sensitivity, and tolerance) that are genetically correlated with Mpdz status and expression, as well as other CNS hyperexcitability states. An innovative feature of this proposal is to combine robust behavioral models of alcohol withdrawal with state-of-the-art strategies to elucidate Mpdz's mechanism of action. MPDZ is thought to regulate 5HT2C and GABAB receptor function. Given the growing body of evidence that dysregulation of GABA and serotonin transmission contributes to alcoholism, we expect that our results will inform developing models and facilitate progress in human alcohol genetics by setting the stage for future translational and mechanistic studies. We have already established that a gene, Mpdz, substantially influences genetic risk for alcohol physiological dependence and associated withdrawal episodes in mice. This proposal is focused on explaining the mechanism by which Mpdz affects alcohol withdrawal, as well as determining its influence on other behavioral responses to alcohol. Given that Mpdz encodes a protein that regulates the function of serotonin and GABA receptors in the brain, and dysregulation of serotonin and GABA function contributes to alcoholism, we expect that the results of this research will facilitate progress in the treatment of alcohol dependence.

描述（由申请人提供）：在大多数慢性医学和精神病疾病中，酒精中毒和酗酒是复杂的因素。酒精生理依赖性和相关的戒断发作被认为构成了一种强大的动机力量，可以使持续的酒精使用/滥用持续，并有助于复发。在人类中，影响酒精生理依赖性和戒断的基因的鉴定非常有限。因此，使用临床依赖性的临床前（动物）模型，即临床状况接近临床状况对于阐明所涉及的基因网络至关重要。我们已经使用这些方法来鉴定NIH-NIAAA室内科学家在人类酗酒人群中研究的小鼠中涉及戒酒的基因（MPDZ）。定量性状基因座（QTL）是含有等位基因（基因）的染色体位点，这些等位基因（基因）会影响定量（复杂）性状，例如酒精生理依赖性和相关戒断。以前，我们证实了染色体（CHR）1、4和11上的QTL，对小鼠的饮酒产生了重大影响。该提案的重点是CHR 4 QTL，对急性和慢性乙醇的撤离有效影响。在当前的资金期间，我们将此QTL映射到1.8 Mb（<1 cm）的间隔（与人类CHR 9P24-P22.3同步），并确定MPDZ（将多个PDZ结构蛋白，MPDZ或MUPPP1编码为定量性状特质基因（QTG），将其编码为多个PDZ结构蛋白，MPDZ或MUPP1）。使用先天性菌株，该菌株在近交遗传背景以及新型MPDZ转基因动物模型上分离该基因座，我们建议继续阐明MPDZ影响戒酒的机制。我们提出以下三个目的：（1）使用病毒介导的基因转移和/或RNA干扰方法，严格检验以下假设：MPDZ在与乙醇戒断有关的电路中的表达实际上会影响戒断严重程度。离散大脑区域中的药理学操纵将提供有关MPDZ及其对乙醇提取的影响的机械信息。 （2）使用神经化学和神经生理学分析提供机械答案，以识别受MPDZ影响的信号转导途径。 （3）使用过高的和MPDZ转基因动物模型，测试MPDZ在对乙醇的行为反应中的作用（即接受饮酒，条件味觉厌恶，共济失调敏感性和耐受性），这些耐受性与MPDZ的状态和表达以及其他CNS症状低下。该提案的创新特征是将戒酒的强大行为模型与最先进的策略相结合，以阐明MPDZ的作用机理。 MPDZ被认为调节5HT2C和GABAB受体功能。鉴于越来越多的证据表明，GABA和5-羟色胺传播失调会导致酒精中毒，我们希望我们的结果通过为未来的翻译和机械研究奠定基础，为发展模型和促进人类酒精遗传学的进步提供了促进。我们已经确定，一个基因MPDZ极大地影响了小鼠酒精生理依赖性和相关戒断发作的遗传风险。该提议的重点是解释MPDZ影响戒酒的机制，并确定其对酒精行为反应的影响。鉴于MPDZ编码一种调节大脑中5-羟色胺和GABA受体功能的蛋白质，以及5-羟色胺和GABA功能的失调会导致酒精中毒，我们希望这项研究的结果将有助于治疗酒精依赖性。