Genetic Vulnerability to Alcohol, Oxidative Homeostasis, and NAC Efficacy

对酒精、氧化稳态和 NAC 功效的遗传脆弱性

基本信息

批准号：
9339472
负责人：
KARI J BUCK
金额：
--
依托单位：
PORTLAND VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9339472
关键词：
Abstinence Acetylcysteine Acute Affect Alcohol abuse Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcohol-Related Disorders Alcoholism Alcohols Amygdaloid structure Animal Model Animals Antioxidants Area Behavior Brain Brain region Candidate Disease Gene Characteristics Chromosomes, Human, Pair 1 Chronic Clinical Complex Congenic Mice Convulsions Data Diagnosis Dose Drug abuse FDA approved Female General Population Genes Genetic Genetic Determinism Genetic Models Genetic Predisposition to Disease Goals High Prevalence Homelessness Homeostasis Hospitalization Hospitals Human Inbreeding Individual Leadership Maps Medical Medical center Mental Health Mental disorders Mitochondria Modeling Motivation Mus Oxidative Phosphorylation Oxidative Stress Pathway Analysis Pathway interactions Patients Pentobarbital Pharmacology Pharmacotherapy Phenotype Physical Dependence Play Pre-Clinical Model Prevention Publishing Quantitative Trait Loci RNA Interference Relapse Research Research Priority Research Proposals Respiratory Chain Rewards Risk Role Saline Stress Substantia nigra structure Systems Biology Testing Time Tissues Treatment Efficacy Variant Veterans Wild Type Mouse Withdrawal Withdrawal Symptom Work addiction alcohol effect alcohol exposure alcohol seeking behavior alcohol testing alcoholism therapy anxiety-like behavior congenic improved outcome male non-alcoholic pleiotropism preference problem drinker public health relevance respiratory response tool transcriptome transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Alcohol dependence (alcoholism) is a common condition in veterans and alcohol abuse is a complicating factor in most chronic medical and psychiatric illnesses. Although alcoholism is substantially (40-60%) genetically determined, the genetic determinants of risk are largely unknown, hindering effective prevention and treatment of dependent individuals. For these reasons and more, there is a clear need to expand pharmacotherapy options for alcohol abuse and dependence to improve outcomes and sustained abstinence. Although no animal model duplicates clinically-defined alcoholism, models for specific factors (including withdrawal/negative effect, which constitutes a motivational force that perpetuates alcohol use and contributes to relapse) are useful to identify potential determinants of liability and pharmacotherapy in humans. A unique strength of this proposal is that we show for the first time that N-acetylcysteine (NAC), an FDA approved antioxidant, mitigates alcohol withdrawal. An important goal of this research proposal is to characterize NAC efficacy to reduce withdrawal (convulsions, anxiety-like behavior) in dependent mice. Using preclinical models, we were also the first to identify quantitative trait loci (QTL) with proven, large effects on alcohol physical dependence and associated withdrawal. One hypothesis that has emerged from our work is that the QTL of largest effect (Adw1) may also affect alcohol seeking behavior. Adw1 is also unique in that it affects alcohol but not pentobarbital withdrawal, providing an important clue to its mechanism of action. Notably, ethanol exposure and withdrawal introduce oxidative stress, while pentobarbital has neutral or anti-oxidative effects in the brain. Some of the most useful tools that we have created thus far are congenic mice with the Adw1 region from a donor strain introgressed onto a different genetic background. These genetic models have been invaluable to map Adw1 to a small interval and identify high-quality candidate genes, the most promising of which (so far) have roles in oxidative homeostasis/stress; and gene co-expression network analyses using Adw1 congenics indicate disruption of the oxidative phosphorylation pathway. Thus, a hypothesis that has emerged from our data is the idea that oxidative homeostasis/stress may play an important role in genetic vulnerability to alcohol physical dependence and withdrawal, and that this pathway may also be a pharmacotherapeutic target to manage withdrawal and beyond. We have now published the first studies of mitochondria respiratory complex activities and organization in the mouse brain and find remarkable genetic differences, providing a framework to gain mechanistic information. Although NAC is thought to affect this pathway, it may have additional actions that could also contribute to its therapeutic efficacy. Using a systems biology network approach, we will assess both possibilities to provide additional mechanistic information. Interestingly, a growing body of evidence implicates natural variation in oxidative homeostasis in genetically influenced differences in mice, disproportionately affecting the brain, so we expect that our results may direct research beyond the addictions.

描述（由申请人提供）：酒精依赖（酒精中毒）是退伍军人的常见状况，滥用酒精是一个复杂的因素，在大多数慢性医学和精神疾病中。酒精中毒是基本确定的，风险的遗传决定剂在很大程度上是未知的，妨碍了有效的预防和治疗依赖的人。对于这些原因，对于这些原因，对于这些原因，有更多的需求可以扩大药物滥用和依赖性的依赖性，并依靠酒精滥用和依赖性。尽管没有动物模型可以重复临床定义的酒精中毒，但特定因素的模型（包括戒断/负面影响，构成了使酒精含量永久使用并有助于缓解的动机力量）对于确定人类中的责任和药物治疗的潜在确定。该提案的一个独特优势是，我们首次表明了FDA批准的抗氧化剂N-乙酰半胱氨酸（NAC）减轻酒精的戒断。该研究建议的一个重要目标是表征NAC效率，以减少依赖小鼠中的戒断（抽搐，类似焦虑行为）。使用临床前模型，我们也是第一个识别局部定量性状（QTL）的人，对酒精的身体依赖性和相关戒断具有很大的影响。我们工作中提出的一个假设是，最大效果（ADW1）的QTL也可能影响寻求酒精的行为。 ADW1的独特之处在于它影响酒精但不影响五叶牙，这为其作用机理提供了重要的线索。值得注意的是，乙醇暴露和戒断会引入氧化应激，而戊巴比妥则在大脑中具有中性或抗氧化作用。迄今为止，我们创建的一些最有用的工具是来自供体菌株的ADW1区域的先天小鼠，这些供体菌株引入了不同的遗传背景。这些遗传模型是无价将ADW1映射到较小间隔并确定高质量候选基因的宝贵的，而最有望（到目前为止）在氧化性稳态/压力中具有作用。基因共表达网络分析使用ADW1友善，表明破坏氧化磷酸化途径。从我们的数据中提出的一个假设是，氧化稳态/压力可能在遗传脆弱性中对酒精物理依赖和戒断的遗传脆弱性起重要作用，并且该途径也可能是管理戒断及以后的药物治疗靶标。现在，我们已经发表了有关小鼠大脑中线粒体呼吸复杂活动和组织的首次研究，并发现显着的遗传差异，提供了一个框架来获得机械信息。尽管NAC被认为会影响这一途径，但它可能会采取其他行动，也可能有助于其治疗效率。使用系统生物学网络方法，我们将评估两种可能性，以提供其他机械信息。有趣的是，越来越多的证据表明，遗传影响小鼠差异的氧化稳态的自然变化，对大脑的影响不成比例，因此我们期望我们的结果可能会导致研究以外的研究。