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：
10454143
负责人：
Dongjun Chung
金额：
$ 78.26万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454143
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 abuse victim 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.

项目摘要阿片类药物滥用是一个严重的全球问题，会影响所有社会的健康，社会和经济福利。阿片类药物使用障碍（OUD）是一种医疗状况，其特征是强迫使用阿片类药物目的地对手当阿片类药物使用结束时，继续使用的后果和戒断综合征的发展。 Oud 涉及对阿片类药物的成瘾和依赖。阿片类药物包括处方药，例如吗啡，可待因，羟考酮和氢可酮以及海洛因等非法药物。虽然动物模型为精确控制环境环境和药物暴露提供严格，方便的手段，并评估行为，基因组，生化和认知变化，有效利用此类模型等有效代理因为人类成瘾仍然受到挑战。媒体行为差异的基因变体的身份实验室动物在很大程度上仍然是未知的，对生理差异的解释很大，了解环境对药物滥用的影响，并阻碍对遗传发现的翻译人类。这种限制突出了对健壮动物进行集成基因组表征的迫切需求该项目的目的是利用阿片类药物滥用研究的急经动物模型，再加上全面的基因组表征，以改善对基本表型和与阿片类药物滥用过渡有关的基因组变化。该项目将参与国际成瘾科学和行为研究，神经生物学，啮齿动物研究领域的专家多学科团队遗传学，计算基因组学，生物信息学以及高吞吐量计算和数据建模完成三个具体目标。在AIM 1中，我们将利用一个经过验证的海洛因自我模型具有扩展访问的给药，产生与药物增加一致的行为表型在药物吸收时期，消费，药物摄入量的动机和寻求药物的升高。将在两个不同地理位置（美国一个，一个在欧洲）进行的动物分层 “易受伤害”“抗性”频谱，目的是对所有个体进行遗传筛查。目标 2，我们将使用测序（GBS）对1,000的基因分型进行全基因组关联研究（GWAS）从两个位置取样的动物。将对最重要的遗传变异进行验证独立的100只动物的验证队列。在AIM 3中，我们将评估遗传的基因组影响通过高通量RNA测序在AIM 2中发现的变体，以评估相关的基因表达功能基因和发现表达定量性状基因座（EQTL）。染色体会议捕获（3C）将使用将EQTL与其靶基因分配为变体及其受调节基因的靶基因。