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。

基本信息

批准号：
10388395
负责人：
Hao Chen
金额：
$ 68.4万
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：
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/10388395
关键词：
Adult Age Analgesics Animal Model Anxiety Artificial Intelligence Behavior Behavioral Model Biological Assay Brain Brain region Candidate Disease Gene Cessation of life Chromatin Chromosome Mapping Complex Computer software Consumption Copy Number Polymorphism Cues DNA Data Data Analyses Data Set Drug Interactions Drug Kinetics Environment Exposure to Extinction (Psychology)Family Foundations Genes Genetic Genetic Variation Genome Genomics Genotype Goals Heritability Hi-C Human Hybrids Hyperalgesia Immersion Inbred Strain Intake Lead Letters Libraries Link Mammals Maps Measures Medial Methods Mind 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 addiction liability analysis pipeline anxiety-like behavior base behavioral phenotyping candidate marker case control cofactor cohort combat connectome design drug action epigenomics forward genetics 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 ranpirnase rat genome reverse genetics sex social deficits trait transcriptome transcriptome sequencing virtual whole genome

项目摘要

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.

羟考酮等处方阿片类药物的稳步增长导致了美国广泛的滥用和死亡。鉴于药物药代动力学在确定滥用可能性方面的重要性，我们设计了一种口服药物操作性大鼠自我给药（SA）程序来模拟大多数人类使用者/滥用者的药物摄入模式尽管遗传变异在易感性中发挥着重要作用，但开始使用口服片剂的羟考酮。阿片类药物成瘾，关于易患阿片类药物成瘾的特定基因和序列变异的数据非常有限阿片类药物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小组 (HRDP)，由 91 个不同的大鼠基因组组成，用于识别影响操作性羟考酮的遗传变异 HRDP 的独特之处在于：1) 含有与人类相似的高水平遗传多样性。人群；2) 提供了一种控制羟考酮暴露和系统研究基因与环境的方法和基因与药物的相互作用；3) 整合多组学“成瘾组”数据：从遗传学到表观基因组学我们有三个目标：目标 1：我们将分析全基因组测序数据。将进行从头组装来定义几乎所有构成可遗传变异的序列变异。使用选定的高影响菌株的链接读取数据（Dovetail Genomics）将生成我们还将生成关键大脑区域的 RNA-seq 数据，以进一步提高这些组装的质量。获得对羟考酮摄入量的机制了解目标 2：使用 HRDP（男女），我们将进行口服表型分析。羟考酮 SA 具有独特的行为模型，还将测试大鼠对疼痛、社交行为、和焦虑样特征 - 羟考酮戒断的所有迹象，重要的是，我们估计了遗传力（h2）。羟考酮摄入量在 0.3 – 0.4 范围内当使用 n=6/性别时，有效 h2 约为 0.8 — 足以满足高水平。目标 3：我们将使用系统遗传学方法来绘制和整合行为表型。将使用正向（QTL）和反向（PheWAS）遗传方法。我们使用新的线性混合模型来使用 GeneNetwork2 绘制和测试具有关键辅因子的候选基因最后，我们通过比较来评估候选基因和生物标志物的翻译相关性。人类成瘾的 GWAS 队列和纵向报告是技术和概念进步的基础。该应用程序是：新的基因组方法与高度多样化的大鼠群体相结合使我们能够快速定义调节阿片成瘾关键阶段的新基因变异很可能是变异的一个子集。我们定义的分子网络将提供连接序列预测框架的关键组成部分人类阿片类药物成瘾的差异和潜在的治疗方法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新型混合啮齿动物绘图面板精确定义 DNA 变异与自愿服用羟考酮之间的因果关系。