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

项目总结 在过去的5-10年里，阿片类药物的流行已经成为美国的全国性危机。目前，几乎没有人 有很好的治疗选择，但对导致癌症风险的潜在机制知之甚少。 成瘾和药物对大脑的影响。这个项目使用老鼠的基因解决了这两个问题 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。 我们将确定羟考酮相关的表型、基因型和RNA在 HXB/BXH RI品系和另外15个有遗传数据的近交系大鼠品系，摘自 杂交大鼠多样性小组(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株在评估的许多表型特征上存在差异 包括羟考酮的自我给药。在目标1中，48个近交系大鼠品系将被评估为 羟考酮相关行为表型，包括止痛措施。数量性状座位(QTL) 与这些行为相关的基因将使用现有的基因数据进行识别。在目标2中，我们将执行RNA 幼稚动物和大鼠伏隔核和杏仁核组织的测序 羟考酮自我给药。这将识别不同菌株的不同基因，这将是关于 根据基因类型确定风险基线，并识别对羟考酮反应不同的基因(共享和非共享 跨品系)。因为基因不是独立运作的，而是在网络和途径中运作，目标3将 采用系统遗传学方法确定与基线差异有关的遗传网络 菌株和对羟考酮自我给药的反应。在所有目标上，我们将比较QTL 区域、RNA表达差异和基因网络路径与该领域中其他人所发现的 补充啮齿动物模型和/或人体研究(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。

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.