Dynamic epigenomic landscape of opioid abuse following early-life adversity

早年逆境后阿片类药物滥用的动态表观基因组景观

• 批准号: 10651607
• 负责人: Tallie Z. Baram
• 金额: $ 70.21万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651607
• 关键词: ATAC-seq; Address; Adopted; Adult; Affect; Amygdaloid structure; Automobile Driving; Behavior; Behavioral; Blood; Brain region; Cell physiology; Cells; Chromatin; Chronic; Complement; Data; Development; Dimensions; Disease; Drug usage; Environmental Risk Factor; Epidemic; Epigenetic Process; Event; Experimental Models; Exposure to; Extinction; Female; Gene Expression; Gene Expression Regulation; Genetic; Genetic Transcription; Genome; Heroin; Heroin Abuse; Incidence; Individual; Intervention; Life; Methods; MicroRNAs; Modeling; Molecular; Motion; Nature; Nucleus Accumbens; Opiate Addiction; Play; Population; Prevention; Process; Psychosocial Stress; Rattus; Recording of previous events; Relapse; Resolution; Risk; Role; Sampling; Self Administration; Sex Differences; Signal Transduction; Technology; Testing; Vulnerable Populations; addiction; cell type; cellular targeting; critical period; disorder prevention; disorder risk; drug of abuse; drug seeking behavior; early life adversity; epidemic response; epigenome; epigenomics; experience; experimental study; extracellular vesicles; gene network; gene regulatory network; heroin use; human data; insight; male; miRNA expression profiling; multiple omics; novel; novel marker; novel therapeutics; opioid abuse; opioid epidemic; opioid overdose; opioid use disorder; predictive marker; sex; single nucleus RNA-sequencing; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY The last decade has seen a devastating epidemic of opioid addiction in the U.S with the fatal opioid overdose incidence doubling in 10 years. Genetic factors clearly contribute to addiction vulnerability, but they alone cannot account for this rise. Therefore, environmental factors must also play role, and their enduring effects would be maximal during sensitive/critical periods early in life. Indeed, early life adversity (ELA) is associated with opioid addiction vulnerability, and in experimental models, it promotes such vulnerability. Although the responsible mechanisms have yet to be elucidated, the enduring nature of changes set in motion by ELA strongly suggest that epigenetic mechanisms may underlie these stable changes. The epigenome is a signal integration platform superimposed on the genome, which is modified by both ELA and drugs of abuse, and which also encodes aspects of sex differences. Epigenetic mechanisms are known to establish stable changes in cell function (via coordinating gene regulation) that give rise to persistently altered behaviors, including drug use and drug seeking behaviors. Thus, understanding epigenetic and transcriptional changes associated with addiction propensity following ELA may answer several key questions about the causes and mechanisms of opioid use disorder (OUD). For example, how is ELA epigenetically encoded, thereby increasing risk for opioid abuse and relapse- associated behaviors? Does heroin differentially affect the epigenome and transcriptome in those with ELA history, promoting this vulnerability? These questions will be addressed here using robust rat models of ELA and of heroin self-administration and relapse. Capitalizing on our findings that ELA augments heroin vulnerability and relapse in a sex-divergent manner4, consistent with human data20-23, we will test the driving hypothesis that both ELA and initial heroin use regulate epigenomic processes, and these, in turn, coordinate gene regulation that ultimately affects cellular signaling, and OUD-like behaviors. The epigenomic and transcriptomic changes induced by ELA and heroin will be determined by employing both bulk- and single-cell multi-omics in selected brain regions at different points in the OUD trajectory. They will be complemented by sampling of CSF and blood extracellular vesicle (EV) miRNA profiles to enable potential development of predictive markers of OUD risk and/or progression. Using state of the art sequencing and analysis methods, we will uncover gene regulatory networks associated with ELA, initial heroin use, and heroin abuse/relapse in females and males. This approach will allow us to identify novel targets for OUD prevention and intervention in vulnerable individuals.

项目摘要 在过去的十年里，美国发生了致命的阿片类药物过量的阿片类药物成瘾的毁灭性流行病。 发病率在10年内翻了一番。遗传因素显然有助于成瘾的脆弱性，但他们本身不能 这一上升的原因。因此，环境因素也必须发挥作用，其持久的影响将是 在生命早期的敏感/关键时期最大。的确，早期生活逆境（ELA）与阿片类药物有关。 成瘾的脆弱性，在实验模型中，它促进了这种脆弱性。虽然负责人 机制尚未阐明，ELA启动的变化的持久性强烈表明， 表观遗传机制可能是这些稳定变化的基础。表观基因组是一个信号整合平台 叠加在基因组上，基因组被ELA和滥用药物修饰，并且还编码 性别差异方面。已知表观遗传机制建立细胞功能的稳定变化（通过 协调基因调控），导致持续改变的行为，包括药物使用和药物寻求 行为。因此，了解与成瘾倾向相关的表观遗传和转录变化， 以下ELA可以回答有关阿片类药物使用障碍的原因和机制的几个关键问题 （OUD）。例如，ELA是如何表观遗传编码的，从而增加阿片类药物滥用和复发的风险- 相关行为？海洛因对ELA患者表观基因组和转录组的影响是否存在差异 历史，促进这种脆弱性？这些问题将在这里使用强大的ELA大鼠模型和 海洛因自我注射和复吸利用我们的发现，ELA增加海洛因的脆弱性， 与人类数据20 -23一致，我们将检验驱动假设，即 ELA和最初的海洛因使用调节表观基因组过程，这些过程反过来又协调基因调节， 最终影响细胞信号和OUD样行为。表观基因组和转录组的变化 ELA和海洛因诱导的细胞凋亡将通过在选定的细胞中采用体细胞和单细胞多组学来确定。 大脑区域在OUD轨迹的不同点。将通过CSF和血液采样进行补充 细胞外囊泡（EV）miRNA谱，以实现OUD风险预测标志物的潜在开发 和/或进展。使用最先进的测序和分析方法，我们将揭示基因调控 网络与ELA，首次使用海洛因，海洛因滥用/复吸的女性和男性。这种方法 将使我们能够确定新的目标，为OUD的预防和干预，在脆弱的个人。