Genetic pathways for impulsivity and drug reinforcement: DNA and transcriptome variation in mice

冲动和药物强化的遗传途径：小鼠 DNA 和转录组变异

基本信息

批准号：
10176439
负责人：
ELEAZAR ESKIN
金额：
$ 54.81万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2017-09-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10176439
关键词：
Animals Antisense RNA Area Behavior Behavioral Bioinformatics Biological Biological Assay Biological Models Brain Brain region Cell physiology Clinical Cocaine Cocaine Abuse Cocaine Dependence Code Complex DNA Data Set Detection Disease Dissection Drug Controls Drug Regulations Drug abuse Equation Foundations Gene Expression Genes Genetic Genetic study Genotype Goals Heritability Hybrids Impulsivity Inbred Strains Mice Inbreeding Incentives International Intravenous Laboratories Learning Link Maps Medial Meiosis Messenger RNA Modeling Molecular Structure Motivation Mus Nucleotides Nucleus Accumbens Pathway Analysis Pathway interactions Pharmaceutical Preparations Phenotype Play Prefrontal Cortex Production Quantitative Evaluations Quantitative Trait Loci RNA RNA Editing RNA Splicing Recombinant Inbred Strain Recombinants Recording of previous events Regulatory Pathway Resolution Resources Rewards Risk Role Single Nucleotide Polymorphism Site Statistical Data Interpretation Structure Substance abuse problem Technology Therapeutic Therapeutic Intervention Tissues Transcript Untranslated RNA Variant Work addiction base behavioral phenotyping brain tissue clinical phenotype cocaine exposure cocaine self-administration disease phenotype drug reinforcement experience gene product genetic variant genome-wide genomic data insight novel phenotypic data public health relevance tool trait transcriptome transcriptome sequencing

项目摘要

PROJECT DESCRIPTION This project will chart with high-resolution the genetic pathways that give rise to defined clinical phenotypes related to cocaine addiction. We will utilize the power of the hybrid mouse diversity panel (HMDP), combined with high quality behavioral phenotyping and massive-scale RNA sequencing, to trace the interconnections from DNA to RNA to clinical trait and provide layered information on the mechanisms of cocaine abuse. The HMDP consists of 100 inbred and recombinant inbred strains and has a wide array of meiotic breakpoints. The panel has been densely genotyped with more than 200,000 single nucleotide polymorphisms (SNPs), allowing very fine mapping of quantitative trait loci (QTLs). Further, the HMDP is genetically stable and renewable and can be assayed for multiple phenotypes, yielding cumulative biological information. We will expand our previous HMDP-based studies of cocaine abuse-related traits by adding massive-scale RNA sequencing (RNA-Seq), in order to detail the genetic control of the pathways to addiction. Our approach offers the distinct advantage of mapping loci for known pathways as well as those involving variant and exotic RNA species. The following aims are proposed: (1) We will quantitate intravenous self-administration of cocaine in HMDP mice. This phenotype is regarded as being one of the most faithful models of cocaine abuse in animals and will allow evaluation of QTLs that regulate addiction-related phenotypes. (2) We will perform RNA-Seq on two key areas of the brain that play a role in the control of drug abuse, the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) shell region. (3) We will analyze the combined datasets with powerful statistical tools to understand the genetic regulation of drug abuse-related phenotypes. These studies will map genetic networks and inter-tissue regulatory pathways for cocaine addiction and suggest new, highly specific therapeutic strategies.

项目描述该项目将用高分辨率绘制产生定义的临床表型的遗传途径与可卡因成瘾有关。我们将利用混合小鼠多样性面板（HMDP）的功能，合并具有高质量的行为表型和大规模的RNA测序，以追踪互连从DNA到RNA再到临床性状，并提供有关可卡因滥用机制的分层信息。这 HMDP由100个近交和重组近交菌株组成，并具有各种减数分裂断裂点。这面板已用超过200,000个单核苷酸多态性（SNP）密集地分型，允许定量性状基因座（QTLS）的非常精细的映射。此外，HMDP在遗传上是稳定且可再生的，并且可以分析多种表型，从而产生累积的生物学信息。我们将扩大我们的以前的基于HMDP可卡因滥用相关性状的研究通过添加大规模的RNA测序（RNA-Seq），以详细详细介绍成瘾途径的遗传控制。我们的方法提供了独特的映射基因座的优点以及涉及变体和外来RNA物种的途径的优势。这提出了以下目的：（1）我们将定量HMDP小鼠中可卡因的静脉内自我给药。这种表型被认为是动物中可卡因滥用最忠实的模式之一，将允许评估调节成瘾相关表型的QTL。（2）我们将在两个关键领域执行RNA-Seq 在控制药物滥用，内侧前额叶皮层（MPFC）和核中发挥作用的大脑伏伏枪（NAC）壳区域。（3）我们将使用强大的统计工具分析合并的数据集了解与药物滥用相关表型的遗传调节。这些研究将绘制遗传网络可卡因成瘾的组织间调节途径，并提出了新的，高度特异的治疗方法策略。