TRANSCRIPTOME AND EPIGENOME MAPPING IN DOPAMINE NEURONS FROM THE OPIOID EXPOSED HUMAN BRAIN

暴露于阿片类药物的人脑多巴胺神经元的转录组和表观基因组图谱

基本信息

批准号：
10653847
负责人：
Schahram Akbarian
金额：
$ 66.08万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10653847
关键词：
3-Dimensional Acute Affect Age Anhedonia Autopsy Bayesian Network Behavior Brain Catalogs Categories Cell Nucleus Cells Cessation of life ChIP-seq Chromatin Chronic Collection Communities Cues DNA Data Data Set Development Diagnosis Dimensions Disease Drug Addiction Drug abuse Drug usage Enhancers Ethnic Origin Etiology Exposure to Fluorescence Functional disorder Gene Expression Genes Genetic Risk Genetic Transcription Genetic Variation Genome Genomic approach Genomics Genotype Goals Guide RNA Hi-C Human Individual Information Networks Maps Mediating Mental disorders Methods Midbrain structure Molecular Conformation NR4A2 gene National Institute of Drug Abuse Neurobiology Neurons Nuclear RNA Opiate Addiction Opioid Pathology Pathway interactions Pharmaceutical Preparations Phenotype Policies Population Principal Investigator Regulation Research Resolution Rewards Small RNA Sorting Source Specimen Stains Subgroup Substance abuse problem Substantia nigra structure System Testing Time Tissues Toxicology Transcript Travel Uncertainty United States National Institutes of Health Untranslated RNA Validation Variant Ventral Tegmental Area Veterans addiction cell type clinical phenotype cohort comorbidity data sharing differential expression dopamine system dopaminergic neuron drug of abuse drug withdrawal dysphoria epigenome epigenome editing epigenomic profiling epigenomics exposed human population gene network genome-wide histone modification individual variation induced pluripotent stem cell knowledge base network models neural circuit neurogenomics neuropsychiatry neurotransmission non-drug opioid abuse opioid exposure opioid overdose phenotypic data prediction algorithm predictive modeling promoter psychiatric genomics reconstruction sex trait transcriptome transcriptome sequencing virtual

项目摘要

Although many cells and neural circuits clearly contribute to opiate and other substance abuse disorder, the path to drug addiction travels through midbrain dopaminergic neurons. Though a rare cell type (it is estimated that a mere 1 of every 200,000 neurons in the human brain is of a dopaminergic phenotype), changes in dopaminergic neurotransmission are thought to play a role in various stages of addiction, from acute reward mechanisms and goal-directed actions, to the development of habitual behavior and increased salience of cues associated with drug use, as well as the anhedonia and dysphoria associated with drug withdrawal. Surprisingly little is actually known about persistent changes in gene expression that presumably underlie the dysfunction of dopamine systems in brain exposed to opiates and other drug of abuse. Our project is centered on three Specific Aims. In Aim #1,we will extract chromatin from immunotagged midbrain dopaminergic neuron nuclei collected by fluorescence-activated sorting from 150 controls and 150 cases diagnosed with opiate abuse and then profile, on a genome-wide scale, the transcriptome and open chromatin landscapes and promoter-enhancer loopings and other types of chromosomal conformations (the ‘3D genome’) in cell type-specific manner. In Aim #2, we will apply integrative genomics approaches and leverage Aim #1 postmortem brain data with population-scale genotypes and phenotypes provided by the Million Veterans Project and the Psychiatric Genomics Consortium to build causal probabilistic networks and predict key drivers within the regulatory non-coding DNA space of the dopaminergic system. In Aim #3, we will validate addiction-relevant cis-regulatory sequences (from Aim #1, #2) with small RNA-guided epigenomic editing systems in cultured human dopaminergic neurons. Collectively, our midbrain dopaminergic neuron- focused project will fill critical voids in the field of human addiction research and human neurogenomics and embark, for the first time, on a deep epigenomic assessment of one of the key cell populations in reward and addiction circuitry.

尽管许多细胞和神经回路显然有助于优化和其他药物滥用障碍，但吸毒的途径通过中脑多巴胺能神经元传播。虽然是一种罕见的细胞类型（估计人脑中每200,000个神经元中只有1个是多巴胺能表型）的变化据认为，多巴胺能神经传递在成瘾的各个阶段都起着作用机制和目标指导的行动，发展习惯行为的发展和提高的显着性与药物使用相关的提示，以及由于戒毒而与药物相关的ANHEDONIA和烦躁不安。令人惊讶的是，关于基因表达的持续变化的实际上知之甚少，这可能是大脑中多巴胺系统的功能障碍暴露于优化和其他滥用药物。我们的项目集中在三个特定目标上。在AIM＃1中，我们将从免疫吸收中提取染色质通过从150个对照和150的荧光激活分类收集的中脑多巴胺能神经元核。被诊断为扩大滥用的病例，然后在全基因组范围内进行转录组和开放的概况染色质景观和启动子增强剂环和其他类型的染色体构象（细胞类型特异性方式的“ 3D基因组”）。在AIM＃2中，我们将采用集成的基因组学方法，并杠杆目标＃1验尸大脑数据具有种群规模的基因型和表型百万退伍军人项目和精神病基因组学联盟，以建立因果概率网络和预测多巴胺能系统调节性非编码DNA空间内的关键驱动因素。在AIM＃3中，我们将验证与成瘾相关的顺式调节序列（来自AIM＃1，＃2），带有小RNA引导的表观基因组学培养的人多巴胺能神经元中的编辑系统。总体而言，我们的中脑多巴胺能神经元 - 专注的项目将填补人类成瘾研究和人类神经基础学领域的关键空隙以及首次启动对奖励和奖励细胞之一的深度基因组学评估成瘾电路。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Single nucleus transcriptomics of ventral midbrain identifies glial activation associated with chronic opioid use disorder.

DOI：
10.1038/s41467-023-41455-8
发表时间：
2023-09-12
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Wei, Julong;Lambert, Tova Y.;Valada, Aditi;Patel, Nikhil;Walker, Kellie;Lenders, Jayna;Schmidt, Carl J.;Iskhakova, Marina;Alazizi, Adnan;Mair-Meijers, Henriette;Mash, Deborah C.;Luca, Francesca;Pique-Regi, Roger;Bannon, Michael J.;Akbarian, Schahram
通讯作者：
Akbarian, Schahram

Opioid deaths involving concurrent benzodiazepine use: Assessing risk factors through the analysis of prescription drug monitoring data and postmortem toxicology.