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

项目摘要 在过去的5-10年里，阿片类药物的流行已经成为美国的一场全国性危机。目前，少数 存在良好的治疗选择，但对导致糖尿病风险的潜在机制知之甚少。 成瘾和药物对大脑的影响。该项目利用大鼠遗传学方法解决了这两个问题。 模型，以确定与阿片类药物使用障碍的发展相关的表型的遗传贡献。 我们将确定羟考酮相关的表型，基因型，和RNA表达的差异， HXB/BXH RI品系和另外15个遗传数据可用的近交系大鼠品系，来自 杂交大鼠多样性小组（HRDP）。我们初步的表型数据表明， SHR/OlaIpcv和BN-Lx/Cub与ACI品系沿着在许多评估的表型性状上不同 包括自己服用羟考酮在目标1中，将评估48个近交系大鼠品系的多个 羟考酮相关的行为表型，包括镇痛措施。数量性状位点 将使用现有的遗传数据来识别与这些行为相关的基因。在目标2中，我们将执行RNA 使用来自幼稚动物和大鼠中的杏仁核和杏仁核的组织进行测序， 羟考酮自我给药。这将确定不同菌株的基因，这将是关于 基因型的基线风险，并确定对羟考酮反应不同的基因（共享和非共享 跨菌株）。因为基因不是独立运作的，而是在网络和途径中工作，Aim 3将 采用系统遗传学方法来确定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 区域，RNA表达差异和基因网络途径与其他人在该领域使用 补充啮齿动物模型和/或人类研究（包括我们的合作者Olivier乔治博士），以便 狭隘地关注优先基因和途径。

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.