Cell Type-Specific Transcriptional and Chromatin Actions of Antipsychotic Drugs

抗精神病药物的细胞类型特异性转录和染色质作用

• 批准号: 8150127
• 负责人: ERIC J. NESTLER
• 金额: $ 27.72万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150127
• 关键词: Adverse effects; Affect; Antipsychotic Agents; Arts; Autopsy; Behavioral; Behavioral Model; Binding; Biochemical; Brain; Brain region; CREB1 gene; Chromatin; Chronic; Clozapine; Corpus striatum structure; DNA Modification Process; Data; Development; Drug Delivery Systems; Drug Exposure; Drug effect disorder; Gene Expression; Genes; Genetic; Global Change; Haloperidol; Histone H3; Histones; Mediating; Mental disorders; Methods; Methylation; Methyltransferase; Molecular; Neurons; Patients; Pharmaceutical Preparations; Population; Prefrontal Cortex; Public Health; Regulation; Rodent Model; Role; Schizophrenia; Tissues; Up-Regulation; base; cell type; chromatin modification; genome wide association study; genome-wide; histone modification; improved; insight; mRNA Expression; novel; novel strategies; novel therapeutics; promoter; response; transcription factor

There is growing evidence that alterations in gene expression contribute to the long-lasting effects of antipsychotic drugs on the brain. Project 4 contributes importantly to our understanding of the molecular actions of antipsychotic drugs by examining these phenomena at the chromatin level, and by thereby providing novel insight into the molecular basis of antipsychotic drug action. Project 4 will first characterize global changes in histone modifications induced by chronic antipsychotic drug exposure within striatal and prefrontal cortical regions of brain. Preliminary data, indicate that repeated haloperidol or clozapine administration increases levels of a repressive form of histone modification, methylation of Lys9 of histone H3, in these two regions. This effect is mediated via the upregulation of a particular Lys9-H3 methyltransferase, G9a. The proposed studies are aimed at characterizing the cell types within these regions where this drug-induced adaptation occurs and exploring its contribution to the behavioral actions of antipsychotic drugs in several rodent models. Using state-of-the-art chromatin methods, Project 4 will then identify the specific genes that show altered Lys9-H3 methylation, or alterations in other histone or DNA modifications, after chronic drug exposure. We also will study the role of two transcription factors, DeltaFosB and CREB, which are induced in striatal and prefrontal regions by antipsychotic drugs. This will include a cell type analysis of transcription factor regulation and altered binding to gene promoters genome-wide in response to drug exposure. By overlaying the results of these analyses with cell-type specific studies of mRNA expression in Projects 1 and 2, and biochemical studies in Project 3, we will identify antipsychotic drug targets with unique precision, and pursue a small number of targets for their functional role in antipsychotic drug action in our behavioral models. Finally, we will validate the regulation of histone modifications, transcription factors, and novel drug targets in postmortem tissue obtained from patients with schizophrenia. Together, these studies will advance our understanding of antipsychotic drug action, and provide novel approaches for the development of new drugs with improved efficacy and side effect profiles.

越来越多的证据表明，基因表达的改变有助于抗精神病药物对大脑的长期影响。项目 4 通过在染色质水平上检查这些现象，为我们理解抗精神病药物的分子作用做出了重要贡献，从而为抗精神病药物作用的分子基础提供了新的见解。项目 4 将首先描述大脑纹状体和前额皮质区域内长期暴露于抗精神病药物引起的组蛋白修饰的整体变化。初步数据表明，重复施用氟哌啶醇或氯氮平会增加这两个区域中组蛋白修饰的抑制形式（即组蛋白 H3 的 Lys9 甲基化）的水平。这种效应是通过特定 Lys9-H3 甲基转移酶 G9a 的上调介导的。拟议的研究旨在表征发生药物诱导适应的这些区域内的细胞类型，并探索其对几种啮齿动物模型中抗精神病药物行为作用的贡献。使用最先进的染色质方法，Project 4 将识别在长期接触药物后表现出 Lys9-H3 甲基化改变或其他组蛋白或 DNA 修饰改变的特定基因。我们还将研究抗精神病药物在纹状体和前额叶区域诱导的两种转录因子 DeltaFosB 和 CREB ​​的作用。这将包括转录因子调节的细胞类型分析以及响应药物暴露而改变的全基因组基因启动子的结合。通过将这些分析的结果与细胞类型特异性研究相叠加 通过项目 1 和 2 中的 mRNA 表达以及项目 3 中的生化研究，我们将以独特的精度识别抗精神病药物靶点，并在我们的行为模型中寻找少量靶点在抗精神病药物作用中的功能作用。最后，我们将验证精神分裂症患者死后组织中组蛋白修饰、转录因子和新药物靶点的调节。总之，这些研究将增进我们对抗精神病药物作用的理解，并且 为开发具有改善功效和副作用的新药提供新方法。