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

• 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
• 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

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.

项目摘要 在过去的5 - 10年中，阿片类药物流行已成为美国的国家危机。目前很少 存在良好的治疗选择，对导致风险的造成风险的基本机制知之甚少 成瘾和药物对大脑的影响。该项目使用大鼠遗传来解决这两个问题 模型以确定与阿片类药物使用障碍发展相关的表型的遗传贡献。 我们将确定与羟考酮相关的表型，基因型和RNA表达差异 HXB/BXH RI菌株和15种其他近交大鼠菌株可获得遗传数据，从 混合大鼠多样性面板（HRDP）。我们的初步表型数据表明创始人菌株 SHR/OLAIPCV和BN-LX/CUB以及ACI菌株在许多评估的表型性状上都不同 包括羟考酮的自我管理。在AIM 1中，将评估48个近交大鼠菌株 羟考酮相关的行为表型，包括镇痛测量。定量性状基因座（QTL） 将使用现有的遗传数据确定与这些行为相关的。在AIM 2中，我们将执行RNA 在幼稚的动物中使用伏隔核和杏仁核的组织进行测序 羟考酮自我管理。这将确定与菌株不同的基因，这将有用 基因型的基线风险，也鉴定出对羟考酮反应不同的基因（共享和取消共享） 跨压力）。因为基因不是独立运行的，而是在网络和路径中工作，AIM 3将 员工一种系统遗传学方法来识别涉及基线差异的遗传网络 菌株和对羟考酮自我给药的反应。在所有目标中，我们将比较QTL 使用其他区域，RNA表达差异和基因网络途径到其他人在现场发现的区域。 完全啮齿动物的模型和/或人类研究（包括我们的合作者奥利维尔·乔治博士） 狭窄地关注优先基因和途径。