Identification of Genetic Variants that Contribute to Compulsive Cocaine Intake in Rats

鉴定导致大鼠强迫性可卡因摄入的遗传变异

基本信息

批准号：
9308367
负责人：
Olivier George
金额：
$ 82.21万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9308367
关键词：
Adrenal Glands Anatomy Animal Model Animals Basic Science Behavior Behavioral Biochemical Biological Blood Blood specimen Brain Cell Culture Techniques Cells Chronic Circadian Rhythms Cocaine Cocaine Dependence Communities Control Animal Data Disease Environment Epigenetic Process Family Study Female Follow-Up Studies Freezing Funding Gene Expression Generations Genes Genetic Genetic Recombination Genetic study Goals Grant Haplotypes Heritability Histocompatibility Human Human Genome Inbred Strains Rats Intake Intravenous Kidney Laboratories Learning Liver Methods Modeling Molecular Mus National Institute of Drug Abuse Neuroanatomy Ovary Pharmacology Pharmacology Study Phenotype Procedures Protocols documentation Quantitative Reverse Transcriptase PCR Rattus Research Infrastructure Research Institute Research Personnel Resolution Resources Risk Sampling Self Administration Spleen Standardization Stress Substance Addiction Substance abuse problem Technology Testing Testis Tissue Banks Tissue Preservation Tissues Training Twin Studies United States National Institutes of Health Western Blotting addiction animal tissue cocaine use cost follow-up food restriction genetic variant genome sequencing genome wide association study induced pluripotent stem cell longitudinal analysis male multidisciplinary neurobiological mechanism new therapeutic target next generation next generation sequencing programs repository research study screening standardize measure trait

项目摘要

Abstract Twin studies suggest that approximately 50% of the vulnerability to cocaine use disorder is determined by genetic factors, but genome-wide association studies (GWAS) in humans have only begun to identify specific genes that confer this risk. One major impediment to studies of cocaine use disorder is the complexity of the phenotype and the 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 increased vulnerability to compulsive cocaine use by performing a GWAS in N/NIH heterogeneous stock rats. We will use the most relevant animal model of cocaine use disorder (i.e., escalation of intravenous cocaine self-administration) and highly standardized measures of controlled and compulsive cocaine self-administration. To increase the impact of these findings and facilitate translational and basic research studies on the mechanisms underlying compulsive cocaine use, we will also establish a data/tissue repository (CocaineBioBank.org) from behaviorally and genetically characterized animals that will allow researchers to further investigate the cellular and molecular mechanisms underlying compulsive cocaine use and identify the biological changes associated with the expression of specific gene variants. 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 cocaine use in male and female outbred rats, (2) identify genes associated with compulsive cocaine use, (3) create the CocainBioBank which will provide free access to brain, kidney, liver, spleen, ovary, testis, adrenal, and blood samples with a variety of tissue preservation protocols that will allow the generation of induced pluripotent stem cells as well as neuroanatomical, molecular, biochemical, and pharmacological studies on behaviorally/genetically characterized animals.

抽象的双胞胎研究表明，大约50％的可卡因使用障碍脆弱性由遗传因素，但是人类全基因组的关联研究（GWAS）才开始确定特定赋予这种风险的基因。可卡因使用障碍研究的一个主要障碍是表型和缺乏对环境变量的控制。我们提出了一种补充方法利用一个多学科的高度协作联盟，将下一代排序与以独特的，多样化的非人类动物模型进行最先进的行为筛查。主要该建议的目标是确定与强迫性脆弱性相关的基因变异可卡因通过在N/NIH异质种群大鼠中进行GWAS来使用。我们将使用最相关的动物可卡因使用障碍的模型（即静脉可卡因自我给药的升级）和高度可卡因自我管理的受控和强迫性可卡因的标准化度量。增加的影响这些发现并促进了关于强迫性基础机制的转化和基础研究可卡因的使用，我们还将建立一个来自行为和行为和一般具有特征的动物，将使研究人员能够进一步研究细胞和分子强迫性可卡因使用的机制，并确定与特定基因变异的表达。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）表征从男性和女性中从受控到强迫性可卡因使用的过渡杂交大鼠，（2）识别与强迫性可卡因使用相关的基因，（3）创建可卡因biobank 将免费获得大脑，肾脏，肝脏，脾脏，卵巢，睾丸，肾上腺和血液样本组织保存方案将允许产生诱导的多能干细胞以及关于行为/遗传学上的神经解剖学，分子，生化和药物研究动物的特征。