Molecular Neurobiology of Human Drug Abuse

人类药物滥用的分子神经生物学

基本信息

批准号：
9312263
负责人：
YASMIN L. HURD
金额：
$ 52.04万
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：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9312263
关键词：
Address Advanced Development Animal Model Behavior Behavioral Binding Biological Brain Brain region Cell Separation Cells Chromatin Communities Computer Simulation Corpus striatum structure Data Data Analyses Data Set Dependence Detection Development Disease Dorsal Drug Addiction Drug abuse Epidemic Epigenetic Process Functional disorder Future Gene Expression Gene Targeting Genes Genetic Polymorphism Genetic Transcription Heroin Heroin Abuse High-Throughput Nucleotide Sequencing Human Impairment Incidence Intervention Investigation Knowledge Link Medial Mediating Messenger RNA Microarray Analysis Mitogen-Activated Protein Kinases Modeling Molecular Molecular Neurobiology Neurons Neurosciences Nuclear Nucleus Accumbens Opiate Addiction Opiates Opioid Pathway interactions Pattern Pharmaceutical Preparations Pharmacology Phosphotransferases Process Proteins Public Health Rattus Recording of previous events Regulation Research Resources Role Self Administration Structure Synapses Synaptic plasticity Time Transcriptional Regulation Translational Research Ursidae Family Validation Vertebral column Viral Work addiction density drug abuser drug seeking behavior experience experimental study genome-wide heroin overdose insight interdisciplinary approach interest mu opioid receptors multidisciplinary nano-string neuropathology neuropsychiatric disorder novel opioid abuse opioid misuse overdose death prescription opiate prescription opioid misuse promoter public health relevance transcription factor transcriptome transcriptome sequencing trend

项目摘要

DESCRIPTION (provided by applicant): Opiate addiction is now a national epidemic marked by an increased incidence of abuse and overdose of heroin and elevated misuse of prescription opioids which also bears a high incidence of overdose death. Despite this growing opiate problem there remains a lack of knowledge about the molecular neuropathology of this human disorder. A fundamental core of our reverse translational research efforts has thus been to fill critical gaps of knowledge by direct investigation of the brains of human heroin abusers. Such efforts have identified the transcription factor ets-like kinase 1 (ELK1) as a central candidate in human heroin abusers. ELK1 disturbance was downstream of the mu opioid receptor (the pharmacological target of heroin metabolites and prescription opiates) and mitogen-activated protein kinase (MAPK) pathway and it was found by in silico analysis of microarray data to target the promoters of a large percentage of down-regulated genes in the nucleus accumbens (NAc) of heroin abusers. Surprisingly, very limited knowledge exist about ELK1 in relation to drug abuse, but this transcription factor has been implicated in other fields in cellular differentiation and synaptic plasticity that are highly relevant to the pathophysiology of addictio disorders. We hypothesize that heroin abuse leads to dysregulated ELK1-mediated transcriptional activity of target genes involved in the reorganization of striatal synapses and tht modulate drug-seeking behaviors. We propose: (1) to determine ELK1-mediated transcriptional regulation in neurons within striatal and mesocorticolimbic brain regions of human heroin abusers by conducting ELK1 ChIP in combination with high throughput sequencing (ChIP-seq) on the nucleus accumbens, dorsal striatum and medial orbitofrontal cortex of heroin abusers. This data will also be integrated with transcriptome analysis to determine the relationship to gene expression. (2) To identify the epigenetic landscape across the ELK1 gene that contributes to its dysregulation in heroin abusers. (3) To investigate the causal role of ELK1 in structural plasticity and heroin seeking behavior by use of animal models. The multidisciplinary approach will expand significant insights about novel targets for treatment interventions and the dataset accrued by this body of work will be a unique and valuable resource to the field given the current lack of such human brain data.

描述（由申请人提供）：阿片成瘾现已成为全国范围内的流行病，其特点是海洛因滥用和过量服用的发生率增加，以及处方阿片类药物的滥用增加，这也导致过量死亡的发生率很高。尽管鸦片问题日益严重，但人们仍然缺乏对这种人类疾病的分子神经病理学的了解。因此，我们逆向转化研究工作的一个基本核心是通过直接研究人类海洛因滥用者的大脑来填补关键的知识空白。这些努力已确定转录因子 ets 样激酶 1 (ELK1) 作为核心候选因子人类海洛因滥用者。 ELK1 紊乱位于 mu 阿片受体（海洛因代谢物和处方阿片类药物的药理学靶点）和丝裂原激活蛋白激酶 (MAPK) 通路的下游，通过微阵列数据的计算机分析发现，ELK1 紊乱针对大部分阿片受体的启动子。海洛因滥用者伏核（NAc）中的基因下调。令人惊讶的是，关于 ELK1 与药物滥用相关的知识非常有限，但这种转录因子已涉及细胞分化和突触可塑性的其他领域，而这些领域与成瘾性疾病的病理生理学高度相关。我们假设海洛因滥用导致 ELK1 介导的靶基因转录活性失调，这些靶基因参与纹状体突触重组并调节药物寻求行为。我们建议：(1) 通过对伏隔核、背侧纹状体和内侧眶额叶进行 ELK1 ChIP 结合高通量测序 (ChIP-seq)，确定人类海洛因滥用者纹状体和中皮质边缘脑区神经元中 ELK1 介导的转录调节海洛因滥用者的皮质。该数据还将与转录组分析相结合，以确定与基因表达的关系。 (2) 确定导致海洛因滥用者体内 ELK1 基因失调的表观遗传景观。 (3)利用动物模型探讨ELK1在结构可塑性和海洛因寻求行为中的因果作用。多学科方法将扩展对治疗干预新目标的重要见解，鉴于目前缺乏此类人脑数据，这项工作积累的数据集将成为该领域独特且有价值的资源。