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The Genetic Basis of Opioid Dependence Vulnerablility in a Rodent Model

啮齿类动物模型中阿片类药物依赖脆弱性的遗传基础

基本信息

批准号：
10223254
负责人：
Dongjun Chung
金额：
$ 92.18万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10223254
关键词：
Advanced Development Affect Age Algorithms Alleles Amygdaloid structure Analgesics Animal Model Animals Area Behavior Behavioral Behavioral Genetics Behavioral Model Biochemical Bioinformatics Biological Brain Diseases Brain region Cessation of life Codeine Consumption Coupled Data Data Linkages Dependence Detection Development Disease Drug Addiction Drug Exposure Drug abuse Economics Etiology Europe Exhibits Face Female Functional disorder Gender Gene Expression Genes Genetic Genetic Screening Genetic Translation Genetic study Genomic approach Genomics Genotype Geographic Locations Geography Goals Health Heritability Heroin High-Throughput RNA Sequencing Hippocampus (Brain)Human Human Genome Hydrocodone Illicit Drugs Individual Inpatients Intake International Italy Laboratory Animals Legal Length of Stay Link Location Maps Mediating Medical Modeling Morphine Motivation Neurobiology Nucleus Accumbens Opiate Addiction Opioid Organism Outcome Oxycodone Pathologic Pharmaceutical Preparations Pharmacologic Substance Phenotype Physiological Population Prefrontal Cortex Prevention strategy Procedures Process Proxy Quantitative Trait Loci Rat Genome Database Rattus Regulation Relapse Research Resistance Rewards Rodent Rodent Model Sampling Science Self Administration Site Societies Substance Addiction Substance Use Disorder Substance Withdrawal Syndrome Substance abuse problem Syntenic Conservation Testing United States National Institutes of Health Validation Variant Ventral Tegmental Area addiction adverse outcome behavioral genomics behavioral phenotyping behavioral study causal variant chromosome conformation capture cognitive change cohort data modeling efficacious treatment gene discovery genetic analysis genetic architecture genetic variant genome wide association study heroin use illicit drug use improved insight knowledge base male multidisciplinary opioid abuse opioid overuse opioid use opioid use disorder phenotypic data pleiotropism prescription pain reliever rat genome response social substance abuse treatment substance use trait transcriptome sequencing transcriptomics welfare

项目摘要

PROJECT SUMMARY Opioid abuse is a serious global problem that affects the health, social and economic welfare of all societies. Opioid use disorder (OUD) is a medical condition characterized by the compulsive use of opioids despite adverse consequences from continued use and the development of a withdrawal syndrome when opioid use ends. OUD involves both addiction to and dependence upon opioids. Opioids include prescription pharmaceuticals such as morphine, codeine, oxycodone and hydrocodone as well as illicit drugs such as heroin. Although animal models provide a rigorous, convenient means to precisely control environmental context and drug exposure, and assess behavioral, genomic, biochemical and cognitive changes, effective utilization of such models as an efficient proxy for human addiction remains challenging. The identities of gene variants that mediate behavioral differences in laboratory animals remain largely unknown, greatly limiting interpretation of physiologic differences and understanding of the environmental effects on drug abuse, and hindering translation of genetic findings to humans. This limitation highlights the urgent need for an integrated genomic characterization of a robust animal model of opioid abuse. The goal of this project is to exploit an outbred animal model of opioid abuse research, coupled with comprehensive genomic characterization, to improve detection of the underlying phenotypic and genomic changes associated with transition to opioid abuse. The project will engage an international multidisciplinary team of experts in the areas of addiction science and behavioral studies, neurobiology, rodent genetics, computational genomics, bioinformatics, and high throughput computing and data modeling to accomplish three Specific Aims. In Aim 1, we will exploit a validated outbred animal model of heroin self- administration with extended access that produces behavioral phenotypes consistent with increased drug consumption, accelerated motivation for drug intake and elevated drug-seeking in periods of drug absence. Animals at two distinct geographical sites (one in the USA and one in Europe) will be stratified across a ‘vulnerable’  ‘resistant’ spectrum with the objective of performing genetic screening on all individuals. In Aim 2, we will carry out a genome-wide association study (GWAS) using genotyping by sequencing (GBS) on 1,000 animals sampled from the two locations. Validation of the most significant genetic variants will be performed in an independent validation cohort of 100 animals. In Aim 3, we will assess the genomic impact of the genetic variants uncovered in Aim 2 via high throughput RNA sequencing to assess gene expression of relevant functional genes and uncover expression quantitative trait loci (eQTLs). Chromosome conformation capture (3C) will be used to physically link an eQTL with its target gene assigning causality to a variant and its regulated gene.

项目摘要类阿片滥用是一个严重的全球性问题，影响到所有社会的健康、社会和经济福利。阿片类药物使用障碍（OUD）是一种医学疾病，其特征是尽管存在不良反应，但仍强迫使用阿片类药物。继续使用的后果和阿片类药物使用结束时戒断综合征的发展。OUD 包括对阿片类药物的成瘾和依赖。阿片类药物包括处方药，如吗啡、可待因、羟考酮和氢可酮以及海洛因等非法药物。虽然动物模型提供一种严格、方便的方法来精确控制环境背景和药物暴露，并评估行为、基因组、生物化学和认知变化，有效利用这些模型作为有效的代理对人类成瘾的研究仍然是一个挑战。调节行为差异的基因变异的身份，实验动物在很大程度上仍然未知，极大地限制了对生理差异的解释，了解环境对药物滥用的影响，并阻碍将遗传研究结果转化为人类这一限制突出了对健壮动物的综合基因组表征的迫切需要阿片类药物滥用的模式。该项目的目标是利用阿片类药物滥用研究的远交动物模型，再加上全面的基因组表征，以提高潜在的表型和与过渡到阿片类药物滥用相关的基因组变化。该项目将聘请国际成瘾科学和行为研究、神经生物学、啮齿类动物遗传学、计算基因组学、生物信息学、高通量计算和数据建模，实现三个具体目标。在目标1中，我们将利用一种经验证的海洛因自体杂交动物模型，延长给药时间，产生与增加药物剂量一致的行为表型吸毒的动机加快，在没有毒品的时期寻求毒品的人数增加。将在两个不同地理位置（一个在美国，一个在欧洲）的动物进行分层， “脆弱”和“耐药”谱，目的是对所有个体进行遗传筛查。在Aim中 2，我们将使用测序基因分型（GBS）对1000名从这两个地点取样的动物。最重要的遗传变异的验证将在 100只动物的独立验证队列。在目标3中，我们将评估基因对基因组的影响。通过高通量RNA测序在Aim 2中发现的变体，以评估相关基因的基因表达。功能基因和揭示表达数量性状基因座（eQTL）。染色体构象捕获（3C）将用于物理连接eQTL与其靶基因，将因果关系分配给变体及其调节基因。