Epigenetic modulation of antipsychotic-induced side effects in aged mice

抗精神病药引起的老年小鼠副作用的表观遗传调节

基本信息

批准号：
8655436
负责人：
Janitza Liz Montalvo-Ortiz
金额：
$ 4万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2014-01-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8655436
关键词：
Address Adult Adverse effects Affect Age Age-Months Aging Agitation Antipsychotic Agents Autopsy Behavior Behavioral Biochemical Biological Assay Bradykinesia Catalepsy Chronic Corpus striatum structure Coupled DRD2 gene Data Deterioration Disease Dopamine Dopamine Receptor Dose Drug effect disorder Drug usage Elderly Epigenetic Process Female Frequencies Gene Expression Genes Haloperidol Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histones Hypermethylation Individual Injection of therapeutic agent Lead Link Liquid substance MS-275 Measures Mediating Mental disorders Messenger RNA Methylation Molecular Mus Pharmaceutical Preparations Physiological Play Population Prefrontal Cortex Promoter Regions Property Proteins Psychotic Disorders Raclopride Radioactivity Regulation Reporting Reverse Transcriptase Polymerase Chain Reaction Severities Symptoms System Tardive Dyskinesia Testing Therapeutic Therapeutic Intervention Time Tissues Valproic Acid Vorinostat Western Blotting age related aged aging brain base behavior test chromatin immunoprecipitation epigenetic marker functional status histone modification improved mRNA Expression male neurochemistry neuropsychiatry novel therapeutics older patient prevent promoter protein expression receptor receptor expression receptor function scintillation spectrometry treatment duration young adult

Address Adult Adverse effects Affect Age Age-Months Aging Agitation Antipsychotic Agents Autopsy Behavior Behavioral Biochemical Biological Assay Bradykinesia Catalepsy Chronic Corpus striatum structure Coupled DRD2 gene Data Deterioration Disease Dopamine Dopamine Receptor Dose Drug effect disorder Drug usage Elderly Epigenetic Process Female Frequencies Gene Expression Genes Haloperidol Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histones Hypermethylation Individual Injection of therapeutic agent Lead Link Liquid substance MS-275 Measures Mediating Mental disorders Messenger RNA Methylation Molecular Mus Pharmaceutical Preparations Physiological Play Population Prefrontal Cortex Promoter Regions Property Proteins Psychotic Disorders Raclopride Radioactivity Regulation Reporting Reverse Transcriptase Polymerase Chain Reaction Severities Symptoms System Tardive Dyskinesia Testing Therapeutic Therapeutic Intervention Time Tissues Valproic Acid Vorinostat Western Blotting age related aged aging brain base behavior test chromatin immunoprecipitation epigenetic marker functional status histone modification improved mRNA Expression male neurochemistry neuropsychiatry novel therapeutics older patient prevent promoter protein expression receptor receptor expression receptor function scintillation spectrometry treatment duration young adult

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项目摘要

The use of psychotropic medications in the elderly population is always challenging due to decreased efficacy and an exacerbated side effects. Thus, there is an urgent need to find new and efficient ways to increase efficacy and to decrease side effects of antipsychotics for aged individuals. Age-related changes epigenetic modulation may contribute to the deterioration of appropriate gene expression induced by antipsychotics. Previous studies have suggested that disruption in receptor functions of dopamine during aging, the primary target of antipsychotic drugs, may be due to changes in gene expression. Age-related changes in the homeostatic tone of the dopaminergic system may be mediated by epigenetic mechanisms, thus revealing a potential reversibility of these effects by pharmacological therapeutic intervention. For this study, we will investigate (1) if age-related decrease of striatal and cortical dopamine 2 (D2) receptor (mRNA and protein levels) are due to histone hypoacetylation and hypermethylation; (2) if increased physiological and behavioral sensitivity to antipsychotic drugs in aged mice is due to decreased D2 gene and protein expression and decreased D2 receptor occupancy and (3) if co-treatment of HDAC inhibitors (valproic acid (VPA) and vorinostat (SAHA)) will decrease haloperidol (HAL)-induced extrapyramidal side effects (EPS) in aged mice by reversing age-related epigenetic effects. Our preliminary findings revealed that co-treatment of HAL with VPA reverses age-related hypoacetylation at the striatal Drd2 promoter region that correlates with decreased D2 receptor protein expression. These changes are associated with decreased HAL-induced EPS behavior. These findings, together with the dissertation proposal, will indicate whether aging reduces histone acetylation and increases histone tri-methylation levels in the striatum and prefrontal cortex that subsequently interfere with the regulation of D2 receptor which is relevant for reduction of EPS. Our study will provide molecular, cellular, pharmacological and behavioral evidence showing that age-related histone modifications affect antipsychotic properties, uncovering the links between aging, epigenetic modulation and antipsychotic drug action. This proposal will help to develop novel therapeutic strategy for aged people, particularly those that suffer from psychiatric disorders.

由于功效降低和恶化的副作用，在老年人群中使用精神药物总是具有挑战性的。因此，迫切需要寻找新的有效方法来提高疗效并减少抗精神病药对老年人的副作用。与年龄相关的变化表观遗传调节可能有助于抗精神病药诱导的适当基因表达恶化。先前的研究表明，衰老过程中多巴胺受体功能的破坏是抗精神病药的主要靶标，这可能是由于基因表达的变化所致。多巴胺能系统与年龄相关的稳态张力的变化可能是通过表观遗传机制介导的，从而揭示了药理治疗干预的潜在可逆性。在这项研究中，我们将研究（1）如果年龄相关的纹状体和皮质多巴胺2（D2）受体（mRNA和蛋白质水平）的减少是由于组蛋白脱乙酰基化和高甲基化引起的；（2）如果衰老小鼠中对抗精神病药的生理和行为敏感性提高是由于D2基因和蛋白质表达的降低以及D2受体占用率降低，并且（3）如果HDAC抑制剂（VPA）（VPA）和vorinostat（saha）降低了Halopericol-Halopericol-Ind-Ind-Ind-Ind-Ind-Ind-Ind-Ind-Ind-Ind-Ind-Ind-Ind-Indiend-IndiN-IndiN-Indiend-Indiend-Ind-Ind-Ind-Indiend Or（3）小鼠通过逆转与年龄相关的表观遗传效应。我们的初步发现表明，HAL与VPA的共同治疗在纹状体DRD2启动子区域逆转与年龄相关的低乙酰化，该降低与D2受体蛋白表达的降低相关。这些变化与HAL诱导的EPS行为降低有关。这些发现以及论文建议将表明衰老是否会减少组蛋白乙酰化并增加纹状体和前额叶皮层中的组蛋白三甲基化水平，这些水平随后会干扰与EPS减少相关的D2受体的调节。我们的研究将提供分子，细胞，药理和行为证据，表明与年龄相关的组蛋白修饰会影响抗精神病药，从而发现衰老，表观遗传调节和抗精神病药作用之间的联系。该建议将有助于为年龄较大的人，尤其是患有精神疾病的人制定新的治疗策略。