Genetics of oxycodone intake in a hybrid rat diversity panel.

混合大鼠多样性小组中羟考酮摄入的遗传学。

• 批准号: 10577836
• 负责人: Hao Chen
• 金额: $ 68.03万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577836
• 关键词: Acceleration; Adult; Age; Analgesics; Animal Model; Anxiety; Artificial Intelligence; Behavior; Behavioral Model; Biological Assay; Brain; Brain region; Breeding; Candidate Disease Gene; Cessation of life; Chromatin; Chromosome Mapping; Complex; Computer software; Consumption; Copy Number Polymorphism; Cues; DNA; Data; Data Set; Drug Addiction; Drug Interactions; Drug Kinetics; Environment; Extinction; Family; Foundations; Genes; Genetic; Genetic Variation; Genome; Genomics; Genotype; Heritability; Hi-C; Human; Hybrids; Hyperalgesia; Immersion; Inbred Strain; Intake; Letters; Libraries; Link; Mammals; Maps; Measures; Medial; Methods; Modeling; Molecular; Molecular Weight; Morphine; Motivation; National Institute of Drug Abuse; Nucleus Accumbens; Opiate Addiction; Opioid; Oral; Oxycodone; Pain; Pattern; Persons; Pharmaceutical Preparations; Phase; Phenotype; Play; Population; Predisposition; Prefrontal Cortex; Procedures; Protocols documentation; Quantitative Trait Loci; Rat Genome Database; Rattus; Recombinant Inbred Strain; Reporting; Research Personnel; Resources; Retrotransposon; Risk; Rodent; Role; Sample Size; Self Administration; Site; Social Behavior; Source; System; Tablets; Tail; Testing; Twin Studies; Variant; Ventral Tegmental Area; Virulent; Withdrawal; abuse liability; addiction; analysis pipeline; anxiety-like behavior; behavioral phenotyping; candidate marker; cofactor; cohort; combat; connectome; design; drug action; epigenomics; forward genetics; gene network; genetic approach; genetic variant; genome sequencing; genome wide association study; genomic data; improved; innovation; insertion/deletion mutation; insight; multiple omics; neurogenomics; new therapeutic target; novel; open source; opioid epidemic; opioid misuse; opioid overdose; opioid use disorder; phenome; pleiotropism; pre-clinical; precision medicine; predictive modeling; prescription opioid; public health emergency; public repository; rat genome; reverse genetics; sex; social deficits; trait; transcriptome; transcriptome sequencing; virtual; whole genome

The steady rise in prescription opioids such as oxycodone has led to widespread abuse and deaths in the US. importance of drug pharmacokinetics in determining abuse potential, we have designed an oral operant rat self-administration (SA) procedure to model the pattern of drug intake of most human users/abusers of oxycodone, who initiate using oral tablets. Although genetic variants play important roles in susceptibility to opioid addiction, very limited data are available regarding specific genes and sequence variants that predispose to opioid addiction, and under what conditions. Given the We propose to use an innovative hybrid rat diversity panel (HRDP), which consists of 91 diverse rat genomes, to identify genetic variants influencing operant oxycodone intake in rats. The HRDP is unique in that it: 1) contains a high level of genetic diversity similar to that of human populations; 2) provides a way to control oxycodone exposure and to systematically study gene-by-environment and gene-by-drug interactions; and 3) integrates multi-omics "addictome" data: from genetics to epigenomics to brain connectomes to treatments. We have three aims: Aim 1: We will analyze whole genome sequencing data to define virtually all sequence variants that underlie heritable variations. De novo assemblies will be conducted using linked-reads data for selected high impact strains. Hi-C data (Dovetail Genomics) will be generated to further improve the quality of these assemblies. We will also generate RNA-seq data for key brain regions to obtain mechanistic insights into oxycodone intake. Aim 2: Using the HRDP (both sexes), we will phenotype oral oxycodone SA with a unique behavioral model. Rats will also be tested for sensitivity to pain, social behaviors, and anxiety-like traits - all signs of oxycodone withdrawal. Critically, we estimated the heritability (h2) of oxycodone intake in the range of 0.3 – 0.4. When using n=6/sex, the effective h2 is ~0.8 —sufficient for high precision mapping. Aim 3: We will use systems genetics methods to map and integrate behavioral phenotypes with sequence and transcriptome data. Both forward (QTL) and reverse (PheWAS) genetic methods will be used. We use new linear mixed models to map and test candidate genes with key cofactors using the GeneNetwork2 platform. Finally, we evaluate the translational relevance of candidate genes and biomarkers by comparison to GWAS cohorts and longitudinal reports of addiction in humans. Technical and conceptual advances that underlie this application are: new genomic methods combined with highly diverse rat populations allow us to quickly define novel gene variants that modulate key phases of opiate addiction. It is highly likely that a subset of variants and molecular networks we define will provide key components of a predictive framework linking sequence differences to human opioid addiction and potential treatments. This project uses new systems genetics approaches, open source genomic data and software, and a new type of hybrid rodent mapping panel to precisely define causal linkages between DNA variation and voluntary oxycodone intake.

处方阿片类药物（例如羟考酮）的稳定增长导致了美国的宽度滥用和死亡。 药物药代动力学在确定滥用潜力方面的重要性，我们设计了一个口头 操纵大鼠自我管理（SA）程序，以建模大多数人类用户/滥用者的药物摄入模式 羟考酮的使用，他使用口服片剂。尽管遗传变异在易感性中起着重要作用 阿片类药物成瘾，有关特定基因和序列变体的非常有限的数据 到Oopioid成瘾，以及在什么条件下。 鉴于 我们建议使用创新的混合大鼠多样性面板 （HRDP）由91个潜水大鼠基因组组成，以鉴定遗传变异影响工作羟考酮 在老鼠中摄入。 HRDP是独一无二的：1）包含类似于人类的遗传多样性的高水平 人口； 2）提供了一种控制氧CoDONE暴露并系统地研究基因环境的方法 和基因相互作用； 3）整合了多媒体“上瘾”数据：从遗传学到表观基因组学到 脑连接到治疗。我们有三个目标：目标1：我们将分析整个基因组测序数据 定义几乎所有基于遗传变体的序列变体。从头大会将进行 使用链接阅读数据作为选定的高冲击菌株。 HI-C数据（燕尾基因组学）将生成 进一步提高这些组件的质量。我们还将生成关键大脑区域的RNA-seq数据 获得对羟考酮摄入的机械洞察力。 AIM 2：使用HRDP（两个性别），我们将表型口服 羟考酮SA具有独特的行为模型。大鼠还将测试对疼痛，社会行为的敏感性， 和动画般的特征 - 所有羟考酮戒断的迹象。至关重要的是，我们估计了遗传力（H2） 羟考酮的摄入量为0.3 - 0.4。当使用n = 6/性别时，有效的H2为〜0.8 - 高 精确映射。目标3：我们将使用系统遗传学方法来映射和整合行为表型 使用序列和转录组数据。将使用前进（QTL）和反向（Phewas）遗传方法。 我们使用新的线性混合模型使用genEnetwork 2与关键辅助因子映射和测试候选基因2 平台。最后，我们通过相比评估了候选基因和生物标志物的转化相关性 GWAS同伙和人类成瘾的纵向报道。基础的技术和概念进步 该应用是：新的基因组方法与高度潜水大鼠的种群相结合，使我们能够快速 定义新型基因变体，以调节优化成瘾的关键阶段。一部分变体很有可能 我们定义的分子网络将提供一个链接序列的预测框架的关键组成部分 人类阿片类药物成瘾和潜在治疗的差异。该项目使用新的系统遗传学 方法，开源基因组数据和软件，以及一种新型的混合啮齿动物映射面板 DNA变异与自愿羟考酮摄入之间的精确定义的因果关系。