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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：成瘾是高度可遗传的神经精神疾病；但是，负责任的遗传因素在很大程度上未知。一个人的基因型和特定环境都可以强大地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）相互作用可有助于成瘾的遗传力。小鼠是理解G X E相互作用的遗传基础的重要模型生物体，从而可以对遗传和环境因素进行实验控制。该提案的主要目的是确定伴随行为特征中G x e相互作用的遗传基础成瘾的渐进阶段。我们观察到在C57BL/6J（B6J）中广泛滥用的阿片类药物（Oxy）和有条件的位置偏好（CPP）测试中的C57BL/6NJ（B6NJ）基质中广泛滥用的阿片类羟考酮（Oxy）的奖励作用中有有效的G X E相互作用。相对于B6J，B6NJ的Oxy-CPP增加了五倍，但只有在训练期间四分之二的笼子伴侣中有2分。相反，当所有四只小鼠都收到氧气时，消除了基因型的作用。因此，根据小鼠的基因型，家庭笼的训练后社会药物环境会对寻求药物行为产生不同的影响。我们开发了一个多阶段成瘾评估方案（MSAAP），以测量B6底层中G x E相互作用的成瘾性状小组，包括奖励，镇痛耐受性以及阿片类药物戒断的情绪影响成分。除了阿片类药物奖励的底层差异外，初步研究还表明，B6NJ与升高和迷宫中B6J的氧气戒断的情绪影响成分增加了三倍。由于B6底物在遗传上几乎是相同的，因此预计MSAAP性状的G X E相互作用的遗传基础有望产生数量性状基因座（QTLS），而定量性状基因座（QTL）具有很少的预测功能变体。为了支持，初步研究表明，B6J X B6NJ-F2降低的复杂性交叉（RCC）可用于识别QTL的QTL，以识别每个位点少于10个预测功能变体的各种复杂性状。在AIM 1中，RCC将用于绘制MSAAP特征中G X E相互作用的遗传基础，并根据有限数量的预测功能变体选择最可能的候选基因，这些功能变体有望构成QTL的基础。在AIM 2中，候选基因将使用转录激活剂样核酸内切酶（Talens）验证，以引入靶向的无效突变并评估其在成瘾性状中G x E相互作用中的作用。在成瘾的多个方面介导G x E相互作用的新型遗传因素的鉴定将增强我们对支持其进展的动态神经生物学机制的理解。这些研究的结果支持开发成瘾的新型预防和治疗策略的长期目标。一个有吸引力的观念是，临床医生有一天会根据患者的基因型和药物滥用的历史环境来确定最合适的治疗方法。