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：
10015254
负责人：
Schahram Akbarian
金额：
$ 71.47万
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/10015254
关键词：
3-Dimensional ATAC-seq Acute Affect Age Anhedonia Autopsy Base of the Brain 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 Human Individual Information Networks Maps Mediating Methods Midbrain structure Molecular Conformation National Institute of Drug Abuse Neurobiology Neurons Nuclear RNA Opiate Addiction Opioid Pathology Pathway interactions Pharmaceutical Preparations Phenotype Play Policies Population Principal Investigator Regulation Research Resolution Rewards Role Small RNA Sorting - Cell Movement Source Spacer DNA 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 base case control cell type clinical phenotype cohort comorbidity data sharing deep sequencing differential expression dopamine system dopaminergic neuron drug of abuse drug withdrawal dysphoria epigenome epigenomics exposed human population 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明显导致阿片类药物和其他药物滥用障碍，药物成瘾的途径是通过中脑多巴胺能神经元（据估计）。人脑中每 200,000 个神经元中只有 1 个具有多巴胺能表型），多巴胺能神经传递被认为在成瘾的各个阶段发挥作用，从急性奖赏机制和目标导向的行动，以形成习惯性行为并提高与吸毒相关的线索，以及与戒毒相关的快感缺乏和烦躁不安。令人惊讶的是，实际上人们对基因表达的持续变化知之甚少，而这些变化被认为是暴露于阿片类药物和其他滥用药物的大脑中多巴胺系统功能障碍。我们的项目以三个具体目标为中心，在目标#1中，我们将从免疫标记中提取染色质。通过荧光激活分选从 150 个对照和 150 个中脑多巴胺能神经元核中收集诊断出阿片类药物滥用的病例，然后在全基因组范围内分析转录组并开放染色质景观和启动子增强子环以及其他类型的染色体构象（ “3D 基因组”）以细胞类型特异性的方式进行。在目标 2 中，我们将应用综合基因组学方法和利用 Aim #1 死后大脑数据以及由百万退伍军人项目和精神病基因组学联盟建立因果概率网络和预测多巴胺能系统的非编码 DNA 调控空间内的关键驱动因素在目标 3 中，我们将。使用小 RNA 引导的表观基因组验证与成瘾相关的顺式调节序列（来自目标 #1、#2）培养的人类多巴胺能神经元中的编辑系统统称为我们的中脑多巴胺能神经元。重点项目将填补人类成瘾研究和人类神经基因组学领域的关键空白首次对奖励和奖励中的一个关键细胞群进行深入的表观基因组评估成瘾电路。