Genetic Vulnerability to Alcohol Withdrawal and Genetically Correlated Behaviors

酒精戒断的遗传脆弱性和遗传相关行为

• 批准号: 7688295
• 负责人: KARI J BUCK
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7688295
• 关键词: 1q23.2; Acute; Address; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Alleles; Animal Model; Animal Testing; Animals; Antioxidants; Anxiety; Barbiturates; Behavior; Behavioral Model; Biological; Biological Factors; Boxing; Brain; Candidate Disease Gene; Cellular Stress; Chromosomes; Chromosomes, Human, Pair 1; Chronic; Clinical; Complex; Congenic Animals; Congenic Mice; Congenic Strain; Consumption; Dependence; Development; Distal; Dose; Drug usage; Environmental Risk Factor; Ethanol; Ethanol dependence; Face; Figs - dietary; Foundations; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genotype; Goals; Human; Human Genetics; Human Identifications; Light; Link; Maps; Measures; Mediating; Medical; Melatonin; Mental Depression; Mental Health; Methods; Mitochondria; Mitochondrial Proteins; Modeling; Molecular Profiling; Mus; National Institute on Alcohol Abuse and Alcoholism; Nitrous Oxide; Noise; Oxidative Stress; Pathway Analysis; Pathway interactions; Pentobarbital; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physical Dependence; Physiological; Population; Pre-Clinical Model; Prevention; Process; Property; Publishing; Quantitative Trait Loci; Relapse; Respiratory physiology; Role; Sample Size; Scientist; Severities; Site; Staging; Substance Withdrawal Syndrome; Symptoms; Tail Suspension; Testing; Translational Research; United States; United States National Institutes of Health; Variant; Veterans; Withdrawal; Work; alcohol exposure; alcohol response; barbituric acid salt; behavior test; congenic; drinking; gene therapy; genome-wide; hypnotic; in vivo; innovation; mouse model; nitrone; pre-clinical; preference; problem drinker; progenitor; protective effect; public health relevance; sedative; tool; trait; translational study; zolpidem

DESCRIPTION (provided by applicant): Alcoholism is a common condition found in veterans and alcohol abuse is a complicating factor in most chronic medical and psychiatric illnesses. Physical dependence and associated withdrawal constitute a powerful motivational force that perpetuates continued alcohol use/abuse and contributes to relapse. In humans, the identification of genes that influence physical dependence and withdrawal has been limited. Thus, the use of preclinical (animal) models of that closely approximate the clinical situation is essential for finding the gene networks involved. In previous work, we identified a gene for alcohol withdrawal in mice that is now being studied in populations of human alcoholics by NIH-NIAAA intramural scientists. Quantitative trait loci (QTL) are chromosome sites containing alleles (genes) that affect complex traits. We have confirmed QTL on chromosomes (Chr) 1, 4, 11 and 19 that have a major influence on alcohol withdrawal in mice. This proposal is focused Chr 1 QTL (Alcdp1/Alcw1) of large effect on withdrawal after chronic and acute alcohol exposure, which we fine-mapped to a 1.1 Mb interval syntenic with human 1q23.2-23.3. Although there is considerable evidence that vulnerability to withdrawal from a variety of sedative-hypnotics have genetic factors in common, Alcdp1/Alcw1 does not influence pentobarbital (PB) withdrawal. This is a crucial clue in identifying the genes(s) QTG) and mechanism by which Alcdp/Alcw1 affects alcohol withdrawal. Candidate QTG prioritization and testing has and will continue to be informed by probing for effects specific to alcohol and not barbiturates. Alcohol exposure induces oxidative stress, and contrasts with a neutral/antioxidative effect of barbiturate exposure in brain. A major strength of this proposal is that we have identified three Alcdp1/Alcw1 candidates that encode mitochondrial proteins with primary effects on oxidative stress. Additionally, a gene network more broadly involved in oxidative stress is trans-regulated by the QTG or a linked gene and may also contribute to the phenotype. An innovative feature of this proposal is to combine robust behavioral models of alcohol withdrawal with state-of-the-art methods to test the role of oxidative stress in response to alcohol. Using a congenic strain that isolates the 1.1 Mb QTL interval on a uniform background, we propose: (1) Test genetically correlated responses to ethanol and other sedative-hypnotics. (2) Test the hypothesis that genotype- dependent differences in chronic ethanol withdrawal are related to oxidative stress and mitochondrial function. (3) Test that genetic vulnerability to acute ethanol (but not PB) withdrawal is related to oxidative stress and mitochondrial function. (4) Compare gene expression profiles to detect QTL associated gene networks and identify key drivers of gene networks or 'hub' genes. (5) To modify oxidative stress and the expression/function of 'hub' genes to test their role in ethanol withdrawal in vivo. We expect that our results will facilitate progress in human genetics by setting the stage for translational/mechanistic studies. PUBLIC HEALTH RELEVANCE: NARRATIVE Abuse and dependence on alcohol and other sedative-hypnotic drugs continue to be substantial mental health problems that face United States veterans. There are a host of biological (genetic) and environmental factors interacting in a complex manner throughout the addictive process to influence alcohol and drug use/abuse and relapse. We recently identified a chromosomal region with a large effect on alcohol physical dependence and associated withdrawal in a preclinical model, and identified a network of genes involved in oxidative stress that plausibly underlies its mechanism of action on withdrawal behaviors. The focus and overall objective of this renewal application is to utilize robust mouse models of alcohol withdrawal to rigorously test the hypothesis that genotype-dependent differences in oxidative stress and mitochondrial respiratory function contribute to genetic susceptibility for severe alcohol physical dependence and associated withdrawal, as well as genetically correlated behaviors (i.e., ethanol preference drinking, and withdrawal from other abused sedative-hypnotic drugs). The animal models developed for the proposed work will provide a powerful foundation for translational research in which gene networks important in determining liability for development of physical dependence and withdrawal in humans are studied, and for developing gene and drug therapies to enhance treatment and prevention.

描述（由申请人提供）： 酒精中毒是在退伍军人中发现的一种常见状况，在大多数慢性医学和精神病中，酗酒是一个复杂的因素。身体依赖和相关的戒断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，影响身体依赖和戒断的基因的鉴定受到限制。因此，使用临床状况的临床前（动物）模型的使用对于查找所涉及的基因网络至关重要。在先前的工作中，我们确定了NIH-NIAAA室内科学家在人类酗酒人群中研究小鼠中戒酒的基因。 定量性状基因座（QTL）是影响复杂性状的等位基因（基因）的染色体位点。我们已经证实了染色体（CHR）1、4、11和19的QTL，这些QTL对小鼠的戒酒产生了重大影响。该提案集中在慢性和急性酒精暴露后的戒断作用中，以CHR 1 QTL（ALCDP1/ALCW1）为重点，我们将其定为与人类1q23.2-23.3同步的1.1 MB间隔。尽管有大量证据表明，从多种镇静性催眠症中退出的脆弱性具有共同的遗传因素，但ALCDP1/ALCW1不影响戊巴比妥（PB）撤离。这是识别基因（S）QTG）和ALCDP/AlcW1影响酒精戒断的机制的关键线索。候选QTG的优先级和测试将通过探测特定于酒精而不是巴比妥类药物的影响来继续告知。酒精暴露会诱导氧化应激，并与巴比妥酸盐暴露在大脑中的中性/抗氧化作用形成对比。该提案的一个主要优势是，我们已经确定了三个alcdp1/alcw1候选物，它们编码线粒体蛋白具有对氧化应激的主要作用。此外，更广泛地参与氧化应激的基因网络由QTG或链接的基因转移，也可能有助于表型。 该提案的创新特征是将戒酒的鲁棒行为模型与最先进的方法相结合，以测试氧化应激对酒精的作用。使用均匀背景上1.1 MB QTL间隔的先天性菌株，我们提出：（1）测试对乙醇和其他镇静催眠杂种药的遗传相关反应。 （2）检验以下假设：慢性乙醇戒断的基因型依赖性差异与氧化应激和线粒体功能有关。 （3）测试是否遗传急性乙醇（但不是Pb）戒断与氧化应激和线粒体功能有关。 （4）比较基因表达谱以检测QTL相关的基因网络并识别基因网络或“枢纽”基因的关键驱动因素。 （5）改变氧化应激和“枢纽”基因的表达/功能，以测试其在体内乙醇戒断中的作用。我们预计我们的结果将通过为翻译/机械研究奠定基础，从而促进人类遗传学的进步。 公共卫生相关性： 叙事滥用和对酒精和其他镇静催眠药的依赖仍然是美国退伍军人面临的重大心理健康问题。在整个成瘾过程中，有许多生物学（遗传）和环境因素以复杂的方式相互作用，以影响酒精和吸毒/滥用和复发。我们最近确定了一个染色体区域，对临床前模型中酒精的物理依赖性和相关戒断具有很大影响，并确定了涉及氧化应激的基因网络，该网络可能构成其对戒断行为的作用机理的基础。这种更新应用的重点和整体目标是利用鲁棒的饮酒模型来严格检验以下假说：基因型依赖于氧化应激和线粒体呼吸功能的差异有助于遗传性，有助于严重的酒精身体依赖性和相关的戒断，以及遗传性的depprience剂，以及遗传性的deptry症，伊斯兰剂，以及遗传性的deptriperiatient and eThanol of ethanol of ethanol。药物）。为拟议工作开发的动物模型将为转化研究提供一个有力的基础，在该研究中，研究了对确定人类物理依赖和戒断的责任重要的基因网络，并为开发基因和药物疗法增强治疗和预防而开发基因和药物疗法。