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）：阿片成瘾现在是一种全国流行病，其标志是滥用和服用过量的海洛因和滥用处方阿片类药物的发病率增加，这也患有过量死亡的发病率。尽管存在这个越来越多的阿片类问题，但仍然缺乏对这种人类疾病的分子神经病理学的了解。因此，我们反向翻译研究工作的基本核心是通过直接调查人类海洛因滥用者的大脑来填补关键知识差距。这样的努力已经确定了转录因子ETS样激酶1（ELK1）作为中心候选者人类海洛因滥用者。 ELK1干扰是MU阿片受体（海洛因代谢物的药理靶标和处方鸦片的药理学靶标）和有丝分裂原活化的蛋白激酶（MAPK）途径的下游，并且在微阵列数据的硅中可以找到它，以靶向下降基因的启动子，在核库use us aCcubs incuneus Accuse beleveration（NAC）的启动子（NAC）中（NAC）。令人惊讶的是，关于ELK1与药物滥用有关的知识非常有限，但是该转录因子与其他领域有关细胞分化和突触可塑性的涉及，这些领域与Addictio疾病的病理生理非常相关。我们假设海洛因滥用会导致与纹状体突触重组的靶基因的ELK1介导的转录活性失调，并调节寻求药物的行为。我们提出：（1）通过通过在原子核，背部纹状体和医生的杂质方向corlosex上进行高吞吐量测序（CHIP-SEQ）结合使用高吞吐量测序（CHIP-SEQ）来确定人海洛因滥用者的纹状体和中皮脑脑区域的ELK1介导的转录调节。该数据还将与转录组分析集成，以确定与基因表达的关系。（2）确定跨ELK1基因的表观遗传景观，导致其在海洛因滥用者中的失调。（3）研究ELK1在结构可塑性和海洛因寻求行为中的因果作用，通过使用动物模型。多学科方法将扩大有关治疗干预措施的新目标的重要见解，鉴于目前缺乏此类人脑数据，这项工作的数据集将是该领域的独特而宝贵的资源。