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Long noncoding RNAs and chromatin regulation in cocaine addiction

可卡因成瘾中的长非编码RNA和染色质调控

基本信息

批准号：
8724105
负责人：
Claes Robert Wahlestedt
金额：
$ 19.19万
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：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8724105
关键词：
Affect Animals Antisense Oligonucleotides Area Attention Attenuated Behavior Behavioral Brain Bromodomain Chromatin Cocaine Cocaine Dependence Complex Data Development Drug Addiction Enzymes Epigenetic Process Future Gene Expression Genes Genetic Transcription Genomics Habits Histones Immunoprecipitation Injection of therapeutic agent Intake Intravenous Laboratories Lead Lysine Mediating Molecular Neurosciences Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Play Process Protein Binding Protein Inhibition Proteins RNA RNA-Protein Interaction Reader Recruitment Activity Regulation Research Rewards Ribonucleoproteins Role Self Administration System Testing Therapeutic Intervention Transcript Transcriptional Activation Untranslated RNA Work addiction anticancer research cell type chromatin remodeling cocaine use deep sequencing drug of abuse gene repression histone acetyltransferase histone modification innovation neuroadaptation neuromechanism novel novel strategies novel therapeutics preference protein complex public health relevance research study response scaffold

项目摘要

DESCRIPTION (provided by applicant): Recent studies have implicated histone-modifying enzymes as key regulators of chromatin state that contribute to cocaine-mediated changes in gene expression, neuroadaptations and seeking behaviors. However, only a limited number of histone-modifying proteins have been studied in the context of addiction, and particularly lacking are studies of epigenetic 'reader' proteins called bromodomains. Of the histone- modifying enzymes implicated in addiction, several are known to form complexes with multiple proteins in order to epigenetically alter transcription, but the underlying mechanisms involved in these interactions remain poorly understood. Growing evidence suggests that cell-type specific long noncoding RNAs (lncRNAs) modulate the function of these epigenetic proteins and/or complexes by acting as scaffolds that help recruit these processes to specific genomic loci. Therefore, investigating the role of lncRNAs in reward-related brain areas offers a fundamentally new approach to identify novel epigenetic mechanisms involved in addiction. In this application we aim to identify novel histone-modifying proteins involved in cocaine intake and determine the interactions between cocaine-related epigenetic targets and lncRNAs that are altered following self-administration of cocaine. We hypothesize that development of cocaine self-administration habit, in part, results from a coordinated change in expression of select histone-modifying proteins and specific lncRNAs that work in concert to epigenetically alter gene transcription. To test this hypothesis, the following aims are proposed: Specific Aim 1: Test the hypothesis that intra-accumbal knockdown of bromodomain genes affects cocaine self-administration. Preliminary data collected from our laboratory indicates that specific bromodomain proteins play an important role in cocaine reward and are increased in the nucleus accumbens following cocaine self-administration. Aim 1 will test whether these bromodomains regulate cocaine self- administration under restricted and extended access conditions. Specific Aim 2: Test the hypothesis that unique long noncoding RNA - protein interactions occur in the nucleus accumbens following cocaine self- administration. Long noncoding RNAs are key regulators of chromatin state, but it is unclear how these transcripts interact with epigenetic proteins to contribute to drug dependence. These studies will identify novel interactions between lncRNAs and histone-modifying proteins in the nucleus accumbens and determine if these associations are altered following yoked, restricted and extended access to cocaine self-administration. By revealing novel epigenetic targets and unchartered epigenetic mechanisms implicated in cocaine intake, a better understanding of these systems may ultimately lead to new therapeutic avenues for cocaine addiction.

描述（由申请人提供）：最近的研究表明，组蛋白修饰酶是染色质状态的关键调节因子，有助于可卡因介导的基因表达，神经适应和寻找行为的变化。然而，只有有限数量的组蛋白修饰蛋白在成瘾的背景下进行了研究，特别是缺乏对称为溴结构域的表观遗传“读者”蛋白的研究。在与成瘾有关的组蛋白修饰酶中，有几种已知与多种蛋白质形成复合物以表观遗传地改变转录，但涉及这些相互作用的潜在机制仍然知之甚少。越来越多的证据表明，细胞型特异性长链非编码rna （lncRNAs）通过作为支架来调节这些表观遗传蛋白和/或复合物的功能，帮助将这些过程招募到特定的基因组位点。因此，研究lncrna在奖励相关脑区中的作用，为识别涉及成瘾的新表观遗传机制提供了一种全新的方法。在这个应用中，我们的目标是鉴定新的组蛋白修饰蛋白参与可卡因的摄入，并确定可卡因相关的表观遗传靶点和lncrna之间的相互作用，这些lncrna在自我给药可卡因后发生改变。我们假设，可卡因自我给药习惯的发展，部分是由于选择组蛋白修饰蛋白和特定lncrna表达的协调变化，这些蛋白和lncrna协同作用，改变表观遗传基因转录。为了验证这一假设，提出了以下目标：具体目标1：验证伏核内溴结构域基因敲低影响可卡因自我给药的假设。我们实验室收集的初步数据表明，特定的溴结构域蛋白在可卡因奖励中起重要作用，并且在可卡因自我给药后伏隔核中增加。目的1将测试这些溴结构域是否在限制和扩展的获取条件下调节可卡因的自我给药。特定目的2：验证在可卡因自我给药后伏隔核中发生独特的长链非编码RNA -蛋白相互作用的假设。长链非编码rna是染色质状态的关键调控因子，但目前尚不清楚这些转录物如何与表观遗传蛋白相互作用，从而导致药物依赖。这些研究将确定伏隔核中lncrna和组蛋白修饰蛋白之间的新相互作用，并确定这些关联是否在有约束、限制和延长可卡因自我给药后发生改变。通过揭示与可卡因摄入有关的新的表观遗传靶点和未知的表观遗传机制，更好地了解这些系统可能最终导致可卡因成瘾的新治疗途径。