Epigenetic Marks of Cocaine Addiction

可卡因成瘾的表观遗传标记

基本信息

批准号：
8532875
负责人：
DEBORAH C. MASH
金额：
$ 69.32万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8532875
关键词：
Acute Age Animal Model Animals Archives Autopsy Behavioral Biochemical Pathway Bioinformatics Biological Blood Brain Brain region Cellular Assay Cessation of life Chemicals Chromatin Chronic Cocaine Cocaine Abuse Cocaine Dependence Cocaine Users Corpus striatum structure Critical Pathways DNA DNA Methylation DSM-IV Dependence Disease Dopamine Dorsal Drug Addiction Drug Exposure Drug abuse Environmental Risk Factor Epigenetic Process Etiology Fluorescence-Activated Cell Sorting Frequencies Funding Gene Expression Gene Expression Profile Gene-Modified Genes Genome Goals Habits Human Individual Intervention Learning Left Link MALDI-TOF Mass Spectrometry Maps Mediating Messenger RNA Methylation Modeling Modification Molecular National Institute of Drug Abuse Neurobiology Neurons Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Probability Psychopathology Quebec Recording of previous events Reverse Transcription Rewards Risk Running Sampling Sampling Studies Sensitivity and Specificity Series Signal Transduction Site Specimen Switch Genes Technology Time Tissues Toxicology Transcript Validation Ventral Striatum addiction base bisulfite brain tissue caudate nucleus cocaine use drug abuser epigenome genome-wide high throughput technology interest meetings methylome neurochemistry neuroimaging neurotoxic screening therapeutic target transcriptome sequencing

项目摘要

Project Summary Multiple interacting genes and environmental factors determine the risk and trajectory of drug addiction. Expression of genes involved in the risk and consequences of addiction is influenced by environmental factors that in many cases are likely to leave persistent chemical modifications (epigenetic marks) in DNA and chromatin. We propose to comprehensively identify in archived postmortem human brain, changes in gene expression and linked epigenetic marks associated with chronic cocaine dependence. We will study two dopamine-dependent brain regions, the dorsal and ventral striatum. We will profile epigenetic marks in cocaine abusers with both short and long-term drug exposures. For analysis of the transcriptome, we will perform whole genome, strand- specific sequencing of mRNA transcripts (RNA-seq). For the DNA methylome, we will use MeDIP or equivalent technology to map the distribution of methyl CpG's at genome- wide and locus specific levels. The ultimate aim of this proposal is to discover which epigenetic changes in brain accompany the transition from cocaine abuse to chronic cocaine dependence. Discovery of cocaine-associated networks and pathways will provide clues to the etiology of cocaine addiction and will identify likely points of intervention in molecular and biochemical pathways that represent potential therapeutic targets.

项目摘要多个相互作用的基因和环境因素决定了吸毒成瘾。表达涉及成瘾的风险和后果的基因受环境因素的影响，在许多情况下可能会持续存在 DNA和染色质中的化学修饰（表观遗传标记）。我们建议全面识别在尸体后的人脑中，基因的变化与慢性可卡因依赖性相关的表达和连接的表观遗传标记。我们将研究两个依赖多巴胺的大脑区域：背侧和腹侧纹状体。我们将在具有短期药物和长期药物的可卡因施虐者中介绍表观遗传标记暴露。为了分析转录组，我们将执行整个基因组，链 mRNA转录物（RNA-SEQ）的特定测序。对于DNA甲基组，我们将使用MEDIP或等效技术来绘制基因组中甲基CpG的分布宽和基因座的特定水平。该提议的最终目的是发现哪个大脑的表观遗传变化伴随着从可卡因滥用到慢性的过渡可卡因依赖性。发现可卡因相关的网络和途径将为可卡因成瘾的病因提供线索，并将确定干预代表潜在治疗的分子和生化途径目标。