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: 7901332
• 负责人: KARI J BUCK
• 金额: $ 5.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-17 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901332
• 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）：酗酒和酗酒是大多数慢性疾病和精神疾病的复杂因素。酒精生理依赖和相关的戒断事件被认为构成了强大的动力，使酒精的持续使用/滥用永久化并导致复发。在人类中，影响酒精生理依赖和戒断的基因的鉴定极其有限。因此，使用非常接近临床情况的酒精生理依赖的临床前（动物）模型对于阐明所涉及的基因网络至关重要。我们使用这些方法鉴定了与小鼠酒精戒断有关的基因 (Mpdz)，NIH-NIAAA 校内科学家目前正在人类酗酒人群中研究该基因。数量性状基因座 (QTL) 是含有等位基因（基因）的染色体位点，可影响数量（复杂）性状，例如酒精生理依赖倾向和相关戒断。此前，我们证实了 1、4 和 11 号染色体 (Chr) 上的 QTL 共同对小鼠的酒精戒断产生重大影响。该提案的重点是 Chr 4 QTL，其已被证明对急性和慢性乙醇戒断有影响。在当前资助期间，我们将该 QTL 精细定位到 1.8 Mb (<1 cM) 间隔（与人类 Chr 9p24-p22.3 同线性），并将 Mpdz（编码多个 PDZ 结构域蛋白、MPDZ 或 MUPP1）鉴定为酒精戒断的数量性状基因（QTG）。使用在近交遗传背景上分离该基因座的同源菌株以及新型 Mpdz 转基因动物模型，我们建议继续阐明 Mpdz 影响酒精戒断的机制。我们提出以下三个目标：（1）使用病毒介导的基因转移和/或RNA干扰方法，严格检验与乙醇戒断有关的电路中的Mpdz表达实际上会影响戒断严重程度的假设。对离散大脑区域的药理学操作将提供有关 MPDZ 及其对乙醇戒断影响的机制信息。 (2) 利用神经化学和神经生理学分析提供机制答案，以确定受 MPDZ 影响的信号转导途径。 (3) 使用同类和 Mpdz 转基因动物模型，测试 Mpdz 在乙醇行为反应中的作用（即接受饮酒、条件性味觉厌恶、共济失调敏感性和耐受性），这些反应与 Mpdz 状态和表达以及其他 CNS 遗传相关过度兴奋状态。该提案的一个创新特点是将稳健的酒精戒断行为模型与最先进的策略相结合，以阐明 Mpdz 的作用机制。 MPDZ 被认为可以调节 5HT2C 和 GABAB 受体功能。鉴于越来越多的证据表明 GABA 和血清素传递失调会导致酗酒，我们预计我们的结果将为开发模型提供信息，并为未来的转化和机制研究奠定基础，从而促进人类酒精遗传学的进展。我们已经确定，Mpdz 基因显着影响小鼠酒精生理依赖和相关戒断发作的遗传风险。该提案的重点是解释 Mpdz 影响酒精戒断的机制，并确定其对酒精其他行为反应的影响。鉴于Mpdz编码一种调节大脑中血清素和GABA受体功能的蛋白质，而血清素和GABA功能失调会导致酒精中毒，我们预计这项研究的结果将有助于酒精依赖治疗的进展。