Identification of genes and genetic networks contributing to opioid use disorder traits in the Hybrid Rat Diversity Panel

杂交大鼠多样性面板中导致阿片类药物使用障碍特征的基因和遗传网络的鉴定

基本信息

批准号：
10403624
负责人：
Ryan K Bachtell
金额：
$ 47.67万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10403624
关键词：
Absence of pain sensation Address Alcohol consumption Amygdaloid structure Analgesics Animals Bayesian Analysis Behavior Behavioral Brain Data Data Set Development Future Gene Expression Genes Genetic Genetic Models Genetic Transcription Genotype Heritability Human Hybrids Hyperalgesia Inbred Strains Rats Individual Intake Knowledge Lead Maps Measures Mechanics Mediator of activation protein Modeling Motivation Neurobiology Nucleus Accumbens Opiate Addiction Opioid Outcome Oxycodone Pain Measurement Pathway Analysis Pathway interactions Pharmaceutical Preparations Phenotype Population Predisposition Prevention strategy Protocols documentation Public Health Quantitative Trait Loci Rattus Recombinant Inbred Strain Risk Rodent Model Role Self Administration System Techniques Testing Time Tissues United States Withdrawal Work addiction base behavioral phenotyping brain tissue differential expression gene environment interaction gene network genetic approach improved neurobiological mechanism opioid epidemic opioid use disorder phenotypic data rat genome response risk variant trait transcriptome sequencing

项目摘要

PROJECT SUMMARY Over the past 5-10 years, the opioid epidemic has become a national crisis in the United States. Currently, few good treatment options exist, and little is known about the underlying mechanisms contributing to risk for addiction and to drug effects on the brain. This project addresses both of these issues using a rat genetic model to identify genetic contributions to phenotypes associated with the development of opioid use disorders. We will identify oxycodone-related phenotypic, genotypic, and RNA expression differences within the HXB/BXH RI strains and 15 additional inbred rat strains for which genetic data are available, drawn from the Hybrid Rat Diversity Panel (HRDP). Our preliminary phenotypic data suggest that the founder strains SHR/OlaIpcv and BN-Lx/Cub, along with the ACI strain, differ on many of the phenotypic traits assessed including the self-administration of oxycodone. In Aim 1, 48 inbred rat strains will be assessed for multiple oxycodone-related behavioral phenotypes, including measures of analgesia. Quantitative trait loci (QTL) associated with these behaviors will be identified using existing genetic data. In Aim 2, we will perform RNA sequencing using tissue from the nucleus accumbens and amygdala in naïve animals and in rats following oxycodone self-administration. This will identify genes that differ by strain, which will be informative about baseline risk by genotype, and also identify genes that differ in response to oxycodone (shared and unshared across strains). Because genes do not operate independently, but work in networks and pathways, Aim 3 will employ a systems genetics approach to identify genetic networks involved in baseline differences across strains and in the response to oxycodone self-administration. Across all aims, we will compare the QTL regions, RNA expression differences, and gene network pathways to those found by others in the field using complementary rodent models and/or human studies (including our collaborator Dr. Olivier George) in order to narrow focus on priority genes and pathways.

项目概要过去5-10年，阿片类药物流行已成为美国的国家危机。存在良好的治疗选择，但对导致风险的潜在机制知之甚少该项目利用大鼠基因来解决这两个问题。模型来识别与阿片类药物使用障碍的发展相关的表型的遗传贡献。我们将鉴定羟考酮相关的表型、基因型和 RNA 表达差异 HXB/BXH RI 品系和 15 个其他近交系大鼠品系（其遗传数据可用）来自我们的初步表型数据表明，杂交鼠多样性小组 (HRDP) 是创始品系。 SHR/OlaIpcv 和 BN-Lx/Cub 以及 ACI 菌株在评估的许多表型性状上存在差异在目标 1 中，将对 48 只近交大鼠品系进行多项评估羟考酮相关的行为表型，包括镇痛数量性状位点（QTL）的测量。在目标 2 中，我们将使用现有的遗传数据来识别与这些行为相关的 RNA。使用来自幼稚动物和大鼠的伏核和杏仁核组织进行测序这将识别不同菌株不同的基因，这将提供有关的信息。按基因型划分的基线风险，并确定对羟考酮反应不同的基因（共享和非共享由于基因不是独立运作的，而是在网络和通路中发挥作用，目标 3 将会。采用系统遗传学方法来识别涉及基线差异的遗传网络在所有目标中，我们将比较 QTL。区域、RNA 表达差异和基因网络途径与该领域其他人使用补充啮齿动物模型和/或人类研究（包括我们的合作者奥利维尔·乔治博士），以便狭隘地关注优先基因和途径。