Center for Genetic Studies of Drug Abuse in Outbred Rats

近交系大鼠药物滥用基因研究中心

• 批准号: 10160842
• 负责人: ABRAHAM A PALMER
• 金额: $ 300.97万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160842
• 关键词: Adolescent; Animal Model; Attention; Behavior; Behavioral; Biological; Brain region; Breeding; Cancer Grant Supplements (P30); Cessation of life; Cocaine; Communities; Complex; Crime; Cues; DNA; Data; Databases; Development; Drug abuse; Ecosystem; Education; Esthesia; Female; Foundations; Funding; Future; Gene Expression; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Recombination; Genetic Techniques; Genetic study; Genotype; Goals; Grant; Growth; Healthcare; Heritability; Human; Human Genetics; Human Genome; Impulsivity; Inbred Strains Rats; Individual; Intravenous; Knowledge; Lead; Maps; Measures; Mental disorders; Methods; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Drug Abuse; Network-based; Nicotine; Pathway interactions; Pharmaceutical Preparations; Phenotype; Pilot Projects; Population; Productivity; Quantitative Genetics; Quantitative Trait Loci; Rattus; Reaction Time; Regulation; Relapse; Research Personnel; Resources; Risk; Role; Sample Size; Self Administration; Sex Differences; Signal Transduction; Social Behavior; Social Reinforcement; Source; Statistical Methods; Substance Use Disorder; System; Techniques; Translations; United States National Institutes of Health; addiction; behavior influence; behavioral phenotyping; behavioral study; career development; cocaine self-administration; cocaine use; cost; deep learning; design; discounting; drug abuse related behavior; effective therapy; genetic analysis; genetic approach; genome wide association study; genome-wide; improved; insight; male; nicotine use; novel; novel strategies; outreach; phenome; phenotypic data; premature; preservation; prevent; psychologic; response; sex; sexual dimorphism; success; sustained attention; tool; trait; transcriptome; transcriptome sequencing; transcriptomics; virtual; web site

Project Summary (Overall) The purpose of this renewal application is to continue the successful activities of our center, which uses quantitative genetic techniques to study the genetic basis of drug abuse-related behaviors in outbred rats. When our center was initially funded in June 2014, our goal was to develop outbred N/NIH heterogeneous stock (HS) rats as a platform for genetic studies of behaviors that were difficult or impossible to study in mice. The first four years of funding have allowed us to establish a vibrant community of investigators using HS rats to study drug abuse and other traits, which we refer to as an ecosystem. This ecosystem includes both the investigators who are directly involved in this renewal application and many others who have obtained separate funding, some from NIDA, and some from other sources. The growth of this ecosystem reflects one of the ways that our center has served as national resource. We are proposing three projects that involved phenotyping HS rats for a variety of traits, including intravenous cocaine and nicotine self-administration, response to novelty, social behavior, reaction time, and delay discounting. Two of those projects are continuations from the prior funding period and are designed to increase our sample size from 1,600 to 3,200 rats per phenotype. We present data showing that such an increase produces an exponential increase in the number of significant findings. This approach parallels human genetics studies of SUD, which have also benefited tremendously from larger sample sizes. We will use these data to conduct genome-wide association studies (GWAS) and a suite of related techniques. In addition, we will measure gene expression in behaviorally naïve rats using RNASeq and use those data to identify expression quantitative trait loci (eQTLs). We will then integrate GWAS and eQTL data in an effort to identify specific genes that influence the behavioral phenotypes. Many of the behavioral domains being studied are known to be sexually dimorphic; our study will use both male and female rats, which will allow us to identify sex differences and sex by genotype interactions. We will also study genetic correlations, perform phenome-wide association studies (PheWAS), transcriptome wide association studies (TWAS) and explore a novel strategy called polygenic transcriptomic risk scores (PTRS), that is intended to allow translation of polygenic signals across species. Project 4 will use a network-based approach to extend our GWAS to account for known biological networks. This proposed renewal also includes a pilot project core to support new directions and take advantage of unforeseen opportunities. Finally we propose an administrative core that supports many activities of the center, including educational, career development and public outreach. The results of these studies will enhance our understanding of the role of genes in a range of psychologically complex behaviors and will provide novel biological insights that may support future efforts at preventing or treating drug abuse.

项目摘要（总体） 此更新应用的目的是继续我们中心的成功活动，该活动使用 数量遗传技术以研究杂种大鼠中与药物滥用相关行为的遗传基础。 当我们的中心最初于2014年6月获得资助时，我们的目标是开发八个非同质性的NIH杂种 库存（HS）大鼠是对小鼠难以或不可能研究的行为遗传研究的平台。 前四年的资金使我们能够使用HS大鼠建立一个充满活力的调查员社区 研究药物滥用和其他特征，我们将其称为生态系统。这个生态系统包括 直接参与此续签申请的调查人员以及许多其他人 单独的资金，一些来自NIDA的资金，有些来自其他来源。该生态系统的增长反映了 我们中心作为国家资源的方式。我们提出了三个涉及的项目 表型HS大鼠针对各种特征，包括静脉可卡因和尼古丁自我给药， 对新颖性，社会行为，反应时间和延迟打折的响应。其中两个项目是 从上一期开始的延续，旨在将我们的样本量从1,600增加到3,200 每个表型大鼠。我们介绍数据，显示这种增加会导致指数增加 许多重要发现。这种方法与SUD的人类遗传学研究类似 从较大的样本量中受益匪浅。我们将使用这些数据进行全基因组关联 研究（GWAS）和一套相关技术。此外，我们将在行为上测量基因表达 使用RNASEQ幼稚大鼠，并使用这些数据识别表达定量性状位置（EQTL）。然后我们会 综合GWAS和EQTL数据是为了识别影响行为表型的特定基因。 已知所研究的许多行为领域是性二态的。我们的研究将两者都使用 男性和雌性大鼠，这将使我们能够通过基因型相互作用来识别性别差异和性别。我们将 还研究遗传相关性，进行全球范围的关联研究（PHEWAS），转录组范围 协会研究（TWA）并探讨了一种新型策略，称为多基因转录组风险评分（PTR）， 这旨在允许跨物种的多基因信号翻译。项目4将使用基于网络的 扩展GWA的方法以说明已知的生物网络。此提议的续约也包括 试点项目核心，以支持新的方向并利用不可预见的机会。最后我们 提案一个支持该中心许多活动的行政核心，包括教育，职业 开发和公共宣传。这些研究的结果将增强我们对 一系列心理复杂行为的基因，将提供新颖的生物学见解 支持未来预防或治疗药物滥用的努力。