Identifying genomic loci related to vulnerability to opioid addiction

识别与阿片类药物成瘾脆弱性相关的基因组位点

基本信息

批准号：
10629206
负责人：
JONATHAN GEWIRTZ
金额：
$ 61.29万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
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/10629206
关键词：
ATAC-seq Acute Addictive Behavior Anhedonia Animal Genetics Animal Model Basic Science Behavior Behavioral Bioinformatics Biological Biological Assay ChIP-seq Chromatin Consumption Cues Data Data Set Drug usage Economics Epigenetic Process Exhibits Exploratory/Developmental Grant for Diagnostic Cancer Imaging Exposure to Extinction Future Gene Expression Gene Expression Regulation Genes Genetic Transcription Genome Genomics Genotype Goals Impulsivity Individual Individual Differences Intake Maps Measures Medial Minority Modeling Modification Molecular Target Morphine National Institute of Drug Abuse Opiate Addiction Opioid Pattern Persons Pharmaceutical Preparations Phase Phenotype Play Predisposition Prefrontal Cortex Prevention Prevention approach Prevention strategy Rattus Regulation Regulator Genes Relapse Research Rodent Model Role Self Administration Severities Sprague-Dawley Rats System Techniques Transcriptional Activation United States National Institutes of Health Variant Vulnerable Populations Withdrawal addiction behavioral economics behavioral phenotyping bioinformatics tool combinatorial drug reinforcement endophenotype epigenetic regulation epigenomics experimental study genetic variant genomic data genomic locus improved indexing individual variation innovation next generation sequencing novel opioid use disorder personalized approach prospective transcriptome sequencing transcriptomics

项目摘要

Between 8-12% of people exposed to opioids develop opioid use disorder (OUD). Developing more effective preventions and treatments for OUD requires a better understanding of genomic and epigenetic mechanisms that underlie individual vulnerability to distinct stages along the OUD trajectory (e.g., initial use, compulsive use, relapse). The overall goal of this proposal is to use an outbred rat model (Sprague-Dawley) to identify novel downstream genes and upstream regulators of gene transcription involved in 3 behavioral phenotypes associated with distinct stages along the OUD trajectory. By comparing rats that show high versus low levels of addiction-like behavior at each stage, we will be able to identify changes in gene expression and their regulation associated specifically with susceptibility to opioid addiction from among the numerous effects of opioids that are unrelated to addiction. Anhedonia produced during withdrawal from acute morphine (i.e., withdrawal-induced anhedonia, WIA) will be used as an addiction phenotype of the earliest phase of OUD, i.e. prior to voluntary drug consumption. We have previously found that WIA is more strongly associated with a range of measures of subsequent i.v. morphine self-administration (SA) than these SA measures are with one another. Economic demand for morphine and reinstatement after extinction will serve as measures of drug reinforcement efficacy and propensity for relapse, respectively, after extensive morphine SA. To identify vulnerability-related genomic targets, we will use Next-Generation Sequencing (NGS) techniques and advanced bioinformatic tools to compare transcriptomic and epigenomic differences in rats exhibiting high versus low levels of WIA (Aim 1), demand (Aim 2) or reinstatement (Aim 3). Our epigenomic assays will map loci of chromosomal accessibility (using ATAC-seq) and of the stable chromatin mark H3K4me3 (using ChIP- seq). We will overlay each of these data sets onto RNA-seq data to identify genes showing differential activation in High- versus Low-Susceptibility rats, as well as upstream regulators of these transcriptional effects. These assays will focus on the medial prefrontal cortex (mPFC), a node within the mesocorticolimbic system that plays a pivotal role in addiction. We will also overlay epigenomic maps derived from our studies onto genotyping data derived from larger studies of Heterogeneous Stock (HS) rats manifesting High- versus Low addiction-related behavioral phenotypes (e.g., drug intake, impulsivity), in other NIDA Animal Genetics Consortium U01/P50 projects. We hypothesize that these comparisons will yield a set of downstream genes and upstream regulators associated with individual differences in early vulnerability to addiction-like behavior and its severity once established. We further hypothesize that our transcriptomic and epigenomic data will provide a viable roadmap for identifying genetic variants from larger genomic datasets associated with individual differences in OUD susceptibility. As such, our studies promise to yield novel genomic and molecular targets for developing more effective, individualized approaches for the prevention and treatment of OUD.

8-12% 接触阿片类药物的人会出现阿片类药物使用障碍 (OUD)。开发更有效 OUD 的预防和治疗需要更好地了解基因组和表观遗传机制这是个人在 OUD 轨迹上不同阶段的脆弱性的基础（例如，初次使用、强迫性使用）使用，复发）。该提案的总体目标是使用远交大鼠模型（Sprague-Dawley）来识别涉及 3 种行为表型的基因转录的新型下游基因和上游调节因子与 OUD 轨迹上的不同阶段相关。通过比较表现出高水平和低水平的老鼠在每个阶段的成瘾样行为中，我们将能够识别基因表达的变化及其与阿片类药物成瘾易感性相关的调节与成瘾无关的阿片类药物。急性吗啡戒断期间产生的快感缺失（即戒断诱发的快感缺失（WIA）将被用作 OUD 最早阶段的成瘾表型，即在自愿服药之前。我们之前发现 WIA 与后续静脉注射的措施范围吗啡自我给药 (SA) 比这些 SA 措施与一种其他。对吗啡的经济需求和灭绝后的恢复将作为毒品的衡量标准广泛使用吗啡 SA 后分别增强疗效和复发倾向。识别与漏洞相关的基因组目标，我们将使用下一代测序（NGS）技术和先进的生物信息工具，用于比较表现出高水平的大鼠的转录组和表观基因组差异与低水平的 WIA（目标 1）、需求（目标 2）或恢复（目标 3）相比。我们的表观基因组分析将绘制染色体可及性位点（使用 ATAC-seq）和稳定染色质标记 H3K4me3（使用 ChIP- 序列）。我们将把这些数据集叠加到 RNA-seq 数据上，以识别显示差异的基因高易感性大鼠与低易感性大鼠的激活，以及这些转录的上游调节因子影响。这些检测将重点关注内侧前额皮质 (mPFC)，即中皮质边缘内的一个节点系统在成瘾过程中发挥着关键作用。我们还将叠加从我们的研究中得出的表观基因组图谱基因分型数据来源于对表现出高与在其他 NIDA 动物遗传学中，与成瘾相关的行为表型较低（例如药物摄入、冲动）联盟 U01/P50 项目。我们假设这些比较将产生一组下游基因以及与早期成瘾行为易感性个体差异相关的上游监管机构及其严重程度一旦确定。我们进一步假设我们的转录组和表观基因组数据将提供一个可行的路线图，用于从与相关的更大的基因组数据集中识别遗传变异 OUD易感性存在个体差异。因此，我们的研究有望产生新的基因组和分子制定更有效、个性化的 OUD 预防和治疗方法的目标。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Individual Differences in Different Measures of Opioid Self-Administration in Rats Are Accounted for by a Single Latent Variable.

大鼠阿片类药物自我给药的不同措施的个体差异由单个潜在变量解释。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Swain, Yayi;Waller, Niels G;Gewirtz, Jonathan C;Harris, Andrew C
通讯作者：
Harris, Andrew C

Behavioral predictors of individual differences in opioid addiction vulnerability as measured using i.v. self-administration in rats.

使用静脉注射测量的阿片类药物成瘾易感性个体差异的行为预测因素

DOI：
发表时间：
2021-04-01
期刊：
影响因子：
4.2
作者：
Swain, Yayi;Gewirtz, Jonathan C;Harris, Andrew C
通讯作者：
Harris, Andrew C

Repeated morphine exposure activates synaptogenesis and other neuroplasticity-related gene networks in the dorsomedial prefrontal cortex of male and female rats.

重复吗啡暴露会激活雄性和雌性大鼠背内侧前额叶皮层的突触发生和其他神经可塑性相关基因网络。

DOI：
发表时间：
2021
期刊：
影响因子：
4.2
作者：
Liu, Shirelle X;Gades, Mari S;Swain, Yayi;Ramakrishnan, Aarthi;Harris, Andrew C;Tran, Phu V;Gewirtz, Jonathan C
通讯作者：
Gewirtz, Jonathan C