Use of Next-Gen Sequencing to Identify Genetic Variants that Influence compulsiveOxycodone Intake in Outbred Rats

使用下一代测序来识别影响远交大鼠强迫性羟考酮摄入的遗传变异

基本信息

批准号：
10010398
负责人：
Olivier George
金额：
$ 0.85万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2019-08-13 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10010398
关键词：
Analgesics Animal Model Animals Behavior Behavioral Biochemical Blood Brain Buprenorphine Chronic Comorbidity DNA Data Development Disease Environment FDA approved Family Study Female Follow-Up Studies Funding Generations Genes Genetic Genetic Recombination Genetic study Genotype Goals Grant Haplotypes Heritability Human Human Genome Hyperalgesia Inbred Strains Rats Individual Infrastructure Intake Intravenous Learning Modeling Molecular Mus National Institute of Drug Abuse Opioid Outcome Oxycodone Pain Pain Measurement Pain Threshold Pharmaceutical Preparations Pharmacology Study Phenotype Population Procedures Protocols documentation Rattus Research Institute Resolution Risk Sampling Self Administration Standardization Stress Substance Addiction Substance abuse problem Technology Tissue Preservation Training Twin Studies United States National Institutes of Health Withdrawal addiction circadian cost epidemiology study follow-up food restriction genetic variant genome wide association study induced pluripotent stem cell longitudinal analysis male multidisciplinary new therapeutic target next generation sequencing opioid use disorder preclinical efficacy repository response screening screening program standardize measure trait

项目摘要

Project SummaryAbstract Epidemiological studies suggest that genetic variability significantly contributes (20-60%) to the analgesic response to opioids and vulnerability to opioid use disorder. However, genome-wide association studies (GWASs) in humans have only begun to identify specific genes that confer this risk. One major impediment to studies of opioid use disorder is the complexity of the phenotype and lack of control of environmental variables. We propose a complementary approach that leverages a multidisciplinary, highly collaborative consortium that combines next-generation sequencing with state-of-the-art behavioral screening in a unique, genetically diverse, nonhuman animal model. The primary goal of this proposal is to identify gene variants that are associated with greater vulnerability to compulsive oxycodone use, tolerance to the analgesic effects of oxycodone, development of withdrawal-induced hyperalgesia, and sensitivity to FDA-approved medications by performing a GWAS in N/NIH heterogeneous stock rats. We will use the most relevant animal model of oxycodone use disorder (i.e., escalation of intravenous oxycodone self-administration) and highly standardized measures of compulsive oxycodone self-administration combined with longitudinal assessments of pain thresholds. This project is likely to have a sustained and powerful impact on the field because it will (1) characterize the transition from controlled to compulsive oxycodone use and its comorbidity with hyperalgesia in male and female outbred rats, (2) identify genes associated with compulsive oxycodone use, the preclinical efficacy of current medication (e.g., buprenorphine), and the analgesic/hyperalgesic effects of chronic oxycodone use, and (3) facilitate follow-up studies by creating a repository that contains brain and blood with a variety of tissue preservation protocols that will facilitate follow-up and replicative studies by allowing the generation of induced pluripotent stem cells and neuroanatomical, molecular, biochemical, and pharmacological studies on behaviorally/genetically characterized animals.

项目摘要流行病学研究表明，遗传变异性显着贡献了镇痛药（20-60％）对阿片类药物的反应和对阿片类药物使用障碍的脆弱性。但是，全基因组关联研究（gwass）在人类中才开始确定赋予这种风险的特定基因。一个主要的障碍阿片类药物使用障碍的研究是表型的复杂性和缺乏对环境变量的控制。我们提出了一种互补的方法，该方法利用了一个多学科，高度协作的财团将下一代测序与最先进的行为筛查结合在独特的，遗传上多样化的非人类动物模型。该提案的主要目标是确定基因变体与更大的强迫羟考酮使用的脆弱性有关，对镇痛作用的耐受性羟考酮，戒断诱导的痛觉过敏的发展以及对FDA批准的药物的敏感性在N/NIH异质库存大鼠中进行GWAS。我们将使用最相关的动物模型羟考酮的使用障碍（即静脉内羟考酮自我给药的升级）和高度标准化强迫性羟考酮自我给药的度量与纵向评估疼痛相结合阈值。该项目可能会对该领域产生持续和强大的影响，因为它将（1）表征从受控羟考酮使用及其合并症的过渡性在雄性和雌性杂种大鼠中，（2）识别与强迫羟考酮有关的基因当前药物（例如丁丙诺啡）的功效，以及慢性的镇痛/高温作用羟考酮的使用，（3）通过创建一个包含大脑和血液的存储库来促进后续研究通过允许的各种组织保存方案将促进随访和复制研究产生诱导的多能干细胞和神经解剖学，分子，生化和关于行为/遗传表征动物的药理研究。