System genetics of menthol and nicotine addiction

薄荷醇和尼古丁成瘾的系统遗传学

基本信息

批准号：
10317100
负责人：
Hao Chen
金额：
$ 65.77万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317100
关键词：
Adolescent Affect African American population Age Algorithms Animal Model Animals Behavior Brain Candidate Disease Gene Caucasians Chromosome Mapping Cigarette Cigarette Smoker Clinical Research Cohort Studies Communities Complex Computer software Control Groups Cues DNA DNA Library Data Dependence Dissection Drug Addiction Drug Controls Drug Interactions Drug Modelings Environment Environmental Impact Esthesia Exhibits Exposure to Extinction (Psychology)Family Genes Genetic Genetic Polymorphism Genetic Variation Genome Genomics Genotype Genotype-Tissue Expression Project Goals Heart Diseases Heritability Human Hybrids Inbred Strain Infusion procedures Intake Intravenous Lead Libraries Link Malignant neoplasm of lung Maps Measures Mediating Medicine Menthol Messenger RNA Metadata Methods Modeling Molecular Molecular Weight Motivation National Institute of Drug Abuse Nicotine Nicotine Dependence Oral Pharmaceutical Preparations Phenotype Population Prevalence Quantitative Trait Loci Rat Genome Database Rattus Recombinant Inbred Strain Relapse Reporting Research Research Personnel Resources Rewards Risk Rodent Sample Size Self Administration Smoke Smoker Smoking Smoking Behavior Speed Standardization Stroke System Testing Tobacco United States National Institutes of Health Variant Visual Work addiction behavioral phenotyping behavioral study candidate marker causal variant cofactor cohort drug craving genetic approach genetic testing genetic variant genome sequencing genome wide association study genomic data health disparity high risk human data innovation insertion/deletion mutation interest neurogenomics new therapeutic target nicotine reward nicotine use open source outcome prediction phenome pleiotropism precision medicine predictive modeling preference preventable death programs public repository ranpirnase rat genome reverse genetics sex trait whole genome

项目摘要

The rat is the most commonly used model organism for behavioral studies of addiction. We propose to establish an innovative hybrid rat diversity panel (HRDP) in this work. The HRDP is unique in that it integrates: 1) a high level of genetic diversity similar to that of admixed human populations; 2) a way to control drug exposures and to systematically study gene-by-environment and gene-by-drug interactions; and 3) a way to integrate "addictome" data across scale: from genetics, genomics, and other molecular data together with key addiction related risks. This work will be a step toward developing experimental resources for precision medicine. The HRDP consists of 91 highly diverse genomes of rats that are all open access and can be used by any investigators to study facet of addiction and in different environments or under different treatments. We will use the HRDP to identify sequence variants that control motivational effects of nicotine with a menthol cue. Approximately 25% of smokers prefer mentholated cigarettes. Clinical studies have shown that menthol facilitates initiation, enhances dependence and makes quitting more difficult. Given the large sample size needed in human studies to identify key sequence variants associated with drug addiction, we argue that animal models provide an efficient means to define and test genetic and molecular mechanisms that contribute to the addiction-enhancing effects of menthol. We developed a rat model of nicotine i.v. self-administration (IVSA) with an oral menthol cue. We found that 1) menthol facilitates the acquisition of nicotine IVSA, 2) rats that receive the menthol cue for nicotine show a strong extinction burst, a model for drug craving, and 3) these rats also demonstrate a strong cue-induced reinstatement, a model of relapse. We also showed that the cooling sensation of menthol functions as a conditioned cue for nicotine reward, and that oral menthol treatment increases brain nicotine accumulation. Critically, in the context of this U01 mechanism, we estimate that heritability of these traits are greater than 0.6. We have three aims: In Aim 1 we conduct whole genome sequencing of the HRDP. We will define all sequence variants that underlie heritable variation using innovative linked-read libraries and de novo assemblies. In Aim 2 we phenotype nicotine IVSA with a menthol cue in adolescent HRDP animals of both sexes with deep replication. We will phenotype nicotine IVSA with a visual cue as a control. Effects of oral menthol on brain nicotine level will be measured. In Aim 3 we use systems genetics methods to map and integrated behavioral phenotypes. Both forward (QTL) and reverse (PheWAS) genetic methods will be used. We will use new linear mixed models to map and test candidate genes with key cofactors (i.e., different cues). Finally, we evaluate the translational relevance of candidate genes and biomarkers by comparison to GWAS cohorts and longitudinal reports of addiction in humans. This U01 will define high impact variants and molecular networks, and will provide a predictive and expandable experimental framework to link sequence differences to critical aspects of human nicotine addiction.

大鼠是成瘾行为研究最常用的模型生物。我们建议在这项工作中建立了一个创新的混合大鼠多样性小组（HRDP）。 HRDP 的独特之处在于它整合了： 1) 与混合人群相似的高水平遗传多样性； 2）控制药物的方法暴露并系统地研究基因与环境以及基因与药物的相互作用； 3）一种方法跨规模整合“成瘾”数据：来自遗传学、基因组学和其他分子数据以及关键数据成瘾相关的风险。这项工作将是朝着开发精确实验资源迈出的一步药品。 HRDP 由 91 个高度多样化的大鼠基因组组成，全部开放获取并可使用由任何研究人员在不同环境或不同治疗下研究成瘾的各个方面。我们将使用 HRDP 来识别通过薄荷醇提示控制尼古丁激励效果的序列变体。大约 25% 的吸烟者更喜欢薄荷香烟。临床研究表明，薄荷醇促进戒烟，增强依赖性，并使戒烟更加困难。鉴于样本量较大人类研究需要识别与毒瘾相关的关键序列变异，我们认为动物模型提供了一种有效的方法来定义和测试有助于的遗传和分子机制薄荷醇的成瘾作用。我们开发了注射尼古丁的大鼠模型。自我管理 (IVSA) 与口服薄荷醇提示。我们发现 1) 薄荷醇促进 IVSA 尼古丁的获取，2) 大鼠接受尼古丁薄荷醇提示的人表现出强烈的消退爆发，这是药物渴望的模型，3）这些大鼠还表现出强烈的提示诱导的恢复，这是一种复发模型。我们还表明薄荷醇的清凉感可作为尼古丁奖励的条件提示，并且口服薄荷醇治疗会增加大脑中尼古丁的积累。至关重要的是，在这种 U01 机制的背景下，我们估计这些性状的遗传力均大于0.6。我们有三个目标：在目标 1 中，我们进行全基因组研究 HRDP 的排序。我们将使用创新的方法定义所有构成可遗传变异的序列变异链接读取库和从头组装。在目标 2 中，我们用薄荷醇提示对尼古丁 IVSA 进行表型分析具有深度复制的两性青少年 HRDP 动物。我们将通过视觉对尼古丁 IVSA 进行表型分析提示作为控制。将测量口服薄荷醇对大脑尼古丁水平的影响。在目标 3 中，我们使用系统绘制和整合行为表型的遗传学方法。正向 (QTL) 和反向 (PheWAS) 将使用遗传方法。我们将使用新的线性混合模型来映射和测试具有关键特征的候选基因辅助因子（即不同的线索）。最后，我们评估候选基因的翻译相关性和与 GWAS 队列和人类成瘾纵向报告进行比较的生物标志物。这个U01将定义高影响力的变体和分子网络，并将提供预测性和可扩展的实验将序列差异与人类尼古丁成瘾的关键方面联系起来的框架。