Mapping G x E Interactions for Addiction Traits in a Reduced Complexity Cross

在降低复杂性的交叉中映射成瘾特征的 G x E 相互作用

• 批准号: 8770129
• 负责人: CAMRON D BRYANT
• 金额: $ 9.36万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8770129
• 关键词: Affect; Affective; Agonist; Analgesics; Animal Model; Behavior; Behavior Therapy; Behavioral; Binge Eating; Biological Assay; Candidate Disease Gene; Cessation of life; Chromosome Mapping; Code; Complex; DNA Sequence; DNA-Binding Proteins; Dependence; Development; Disease; Dose; Drug Targeting; Drug abuse; Emotional; Environment; Environmental Risk Factor; Equilibrium; Exons; Gene Targeting; Genes; Genetic; Genomics; Genotype; Goals; Healthcare; Heritability; Home environment; Income; Individual; Injection of therapeutic agent; Knockout Mice; Knowledge; Law Enforcement; Lead; Letters; Maps; Measures; Mediating; Messenger RNA; Mus; Mutant Strains Mice; Opiate Addiction; Opioid; Oxycodone; Partner in relationship; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Physiological; Productivity; Property; Protocols documentation; Public Health; Quantitative Trait Loci; Relapse; Relative (related person); Rewards; Role; Staging; Symptoms; Technology; Testing; Training; Transcription Coactivator; Validation; Variant; Withdrawal; Work; addiction; alcohol use disorder; base; cost; design; drug of abuse; drug reward; drug seeking behavior; embryo cell; endogenous opioids; endonuclease; gene function; improved; innovation; mortality; mu opioid receptors; neurobiological mechanism; neuropsychiatry; novel; null mutation; opioid abuse; opioid withdrawal; preference; prevent; public health relevance; response; social; socioeconomics; trait; treatment strategy; zygote

DESCRIPTION (provided by applicant): The addictions are highly heritable neuropsychiatric diseases; however, the responsible genetic factors remain largely unknown. Both an individual's genotype and the particular environment can powerfully influence the subjective and physiological response to drugs of abuse. Accordingly, gene x environment (G x E) interactions are hypothesized to contribute substantially to the heritability of the addictions. Mice serve as a important model organism for understanding the genetic basis of G x E interactions, permitting experimental control over genetic and environmental factors. The primary objective of this proposal is to identify the genetic basis of G x E interactions in behavioral traits that accompany the progressive stages of addiction. We observed a potent G x E interaction in the rewarding effect of the widely abused opioid oxycodone (OXY) in C57BL/6J (B6J) and C57BL/6NJ (B6NJ) substrains in the conditioned place preference (CPP) test. B6NJ showed up to a five-fold increase in OXY-CPP relative to B6J, but only when two out of four cage mates received OXY during training. In contrast, when all four mice received OXY, the effect of genotype was eliminated. Thus, the post-training social drug environment of the home cage can exert divergent effects on drug seeking behavior, depending on the genotype of the mice. We developed a multi-stage addiction assessment protocol (MSAAP) to measure a panel of addiction traits for G x E interactions in B6 substrains, including reward, analgesic tolerance, and the emotional-affective component of opioid withdrawal. In addition to substrain differences in opioid reward, preliminary studies indicate a three-fold increase in the emotional-affective component of OXY withdrawal in B6NJ versus B6J in the elevated plus maze. Because B6 substrains are nearly genetically identical, mapping the genetic basis of G x E interactions for MSAAP traits is expected to yield quantitative trait loci (QTLs) that possess very few predicted functional variants. In support, preliminary studies demonstrate that a B6J x B6NJ- F2 Reduced Complexity Cross (RCC) can be used to identify QTLs for diverse complex traits that contain fewer than 10 predicted functional variants per locus. In Aim 1, the RCC will be used to map the genetic basis of G x E interactions in MSAAP traits and select the most likely candidate genes based on the limited number of predicted functional variants that are expected to underlie the QTLs. In Aim 2, candidate genes will be validated using transcription activator-like endonucleases (TALENs) to introduce targeted null mutations and assess their role in G x E interactions in addiction traits. The identification of novel genetic factors mediating G x E interactions in multiple facets of addiction will enhance our understanding of the dynamic neurobiological mechanisms that support its progression. The results of these studies support the long-term goal of developing novel preventative and treatment strategies for addiction. An attractive notion is that clinicians will one day determine the most appropriate treatment based on both the patient's genotype and historical environment of drug abuse.

描述（申请人提供）：成瘾是高度遗传性的神经精神疾病；然而，造成这种情况的遗传因素在很大程度上仍然未知。个体的基因型和特定环境都会强烈影响对滥用药物的主观和生理反应。因此，假设基因 x 环境 (G x E) 相互作用对成瘾的遗传性有重大贡献。小鼠是了解 G x E 相互作用的遗传基础的重要模型生物，允许对遗传和环境因素进行实验控制。该提案的主要目标是确定伴随行为特征的 G x E 相互作用的遗传基础 成瘾的渐进阶段。我们在条件性位置偏好 (CPP) 测试中，在 C57BL/6J (B6J) 和 C57BL/6NJ (B6NJ) 亚株中观察到广泛滥用的阿片类药物羟考酮 (OXY) 的奖励效应中存在有效的 G x E 相互作用。相对于 B6J，B6NJ 的 OXY-CPP 增加了五倍，但前提是四分之二的笼子伴侣在训练期间接受了 OXY。相反，当所有四只小鼠都接受 OXY 治疗时，基因型的影响就被消除了。因此，根据小鼠的基因型，训练后的笼舍社会药物环境会对药物寻求行为产生不同的影响。我们开发了多阶段成瘾评估方案 (MSAAP)，以测量 B6 亚品系中 G x E 相互作用的一组成瘾特征，包括奖励、镇痛耐受性和阿片类药物戒断的情绪情感成分。除了阿片类药物奖励的亚系差异外，初步研究表明，在高架十字迷宫中，B6NJ 与 B6J 相比，OXY 戒断的情绪情感成分增加了三倍。由于 B6 亚系在遗传上几乎相同，因此绘制 MSAAP 性状 G x E 相互作用的遗传基础预计会产生具有很少预测功能变异的数量性状基因座 (QTL)。作为支持，初步研究表明，B6J x B6NJ-F2 降低复杂性杂交 (RCC) 可用于识别每个基因座包含少于 10 个预测功能变异的不同复杂性状的 QTL。在目标 1 中，RCC 将用于绘制 MSAAP 性状中 G x E 相互作用的遗传基础，并根据预计构成 QTL 的有限数量的预测功能变异来选择最可能的候选基因。在目标 2 中，将使用转录激活剂样核酸内切酶 (TALEN) 来验证候选基因，以引入靶向无效突变并评估它们在成瘾性状中 G x E 相互作用中的作用。在成瘾的多个方面介导 G x E 相互作用的新遗传因素的鉴定将增强我们对支持成瘾进展的动态神经生物学机制的理解。这些研究的结果支持了开发新的成瘾预防和治疗策略的长期目标。一个有吸引力的想法是，临床医生有一天将根据患者的基因型和药物滥用历史环境确定最合适的治疗方法。