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：
9768050
负责人：
Hao Chen
金额：
$ 55.31万
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/9768050
关键词：
Adolescent Affect African American Age Algorithms Animal Model Animals Behavior Behavioral 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 Genetic screening method 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 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 study candidate marker causal variant cofactor cohort drug craving genetic approach genetic variant genome database genome sequencing genome wide association study genomic data health disparity high risk human data innovation insertion/deletion mutation interest neurogenomics new therapeutic target nicotine use open source outcome prediction phenome pleiotropism precision medicine predictive modeling preference preventable death programs ranpirnase rat genome repository 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创新的混合大鼠多样性面板（HRDP）。 HRDP是独特的，因为它集成了： 1）高水平的遗传多样性类似于混合人群的遗传多样性； 2）一种控制药物的方法暴露并系统地研究基因环境和逐个药物相互作用的基因； 3）一种方法整合范围内的“上瘾”数据：从遗传学，基因组学和其他分子数据和关键与成瘾有关的风险。这项工作将是开发实验资源的一步药品。 HRDP由91个高度多样的大鼠基因组组成，这些大鼠都是开放式通道，可以使用由任何研究人员研究成瘾的方面，在不同的环境或不同的治疗方法中。我们将使用HRDP来识别控制尼古丁用薄荷醇提示控制动机作用的序列变体。大约25％的吸烟者喜欢薄荷香烟。临床研究表明薄荷醇促进启动，增强依赖性并使退出更加困难。考虑到大样本量在人类研究中需要确定与药物成瘾相关的关键序列变体，我们认为动物模型提供了一种有效的方法来定义和测试遗传和分子机制对薄荷醇的成瘾增强作用。我们开发了尼古丁i.v.的大鼠模型自我管理（IVSA）带有口服薄荷醇提示。我们发现1）薄荷醇促进尼古丁IVSA的获取，2）大鼠接受尼古丁的薄荷醇提示表现出强烈的灭绝爆发，一种渴望毒品的模型，3）大鼠还表现出强大的提示诱导的恢复原状，这是一种复发模型。我们还表明了薄荷醇的冷却感觉是尼古丁奖励的条件提示，而口服薄荷醇治疗增加了脑尼古丁的积累。至关重要的是，在这种U01机制的背景下，我们估计这些特征的遗传力大于0.6。我们有三个目标：在目标1中，我们进行整个基因组 HRDP的测序。我们将定义所有使用创新的遗传变异构成的序列变体链接阅读的库和从头组装。在AIM 2中，我们表型尼古丁IVSA，带有薄荷醇提示两性的青少年hrdp动物都具有深刻的复制。我们将带有视觉的表型尼古丁IVSA 提示作为控制。将测量口服薄荷醇对脑尼古丁水平的影响。在AIM 3中，我们使用系统绘制和整合行为表型的遗传学方法。向前（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绘制和测试候选基因的基因辅因子（即不同的提示）。最后，我们评估了候选基因的翻译相关性和与GWAS同伴和人类成瘾的纵向报道相比，生物标志物。这个U01会定义高影响变体和分子网络，并将提供可预测性且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。