DHHC 15 palmitoylation modulates striatal dopamine system

DHHC 15 棕榈酰化调节纹状体多巴胺系统

基本信息

批准号：
8770451
负责人：
TAO WANG
金额：
$ 24.3万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8770451
关键词：
Acute Adult Affect Agonist Amphetamines Animal Model Attention deficit hyperactivity disorder Biological Assay Biotin Brain imaging Brain region COS Cells Child Chronic Clinical Clinical effectiveness Collaborations Core Facility Corpus striatum structure Defect Development Dopamine Dopamine Antagonists Dopamine D1 Receptor Dopamine Receptor Drug Targeting Drug abuse Family Genetic High Pressure Liquid Chromatography Human Hydrophobicity Hyperactive behavior Immunoblotting Immunofluorescence Immunologic In Vitro Inbreeding Individual Kinetics Knockout Mice Label Letters Life Lipids Mediating Membrane Mental Depression Mental disorders Metabolic Metabolism Methylphenidate Microdialysis Modification Molecular Morphology Motivation Movement Mus Mutant Strains Mice National Institute of Drug Abuse Neurons Neurotransmitters Norepinephrine Phenotype Play Post-Translational Protein Processing Prevalence Proteins Proteomics Regulation Research Rewards Risk Role School-Age Population Serotonin Signal Transduction Substantia nigra structure Substrate Specificity Symptoms Synapses System Tissues Transferase Treatment Protocols Tyrosine 3-Monooxygenase Vesicle base dopamine system dopamine transporter dopaminergic neuron effective therapy executive function extracellular frontal lobe in vivo inhibitor/antagonist insight mouse model neurobiological mechanism neuron loss novel palmitoylation postsynaptic density protein presynaptic protein transport psychostimulant public health relevance response reuptake standard care tandem mass spectrometry trafficking

项目摘要

DESCRIPTION (provided by applicant): Attention deficit hyperactivity disorder (ADHD) is a common psychiatric disorder with a prevalence of 3- 7% in school-aged children and 4% in adults worldwide. Psychostamulants are extensively used for treatment of ADHD symptoms with a favorable response. However, variable clinical effectiveness, non- responsiveness and tolerance to standard treatment regimens, and increasing risks for drug abuse and mental illnesses later in life continue to be serious concerns. Dysregulations of striatal dopamine (DA) system in ADHD are widely supported by clinical, genetic, and brain imaging studies in humans and animal models, and by clinical effectiveness of psychostimulants. Despite decades of research, the precise neurobiological mechanisms for ADHD remain poorly understood, which severely hampers the development of novel, safe, and effective therapies. Palmitoylation is a reversible lipid post-translational modification catalyzed by a family of DHHC-domain palmitoyltransferases. We have generated a line of DHHC15-knockout mice that show hyperactivity and reduced DA levels in striatum. Hyperactivity in the mutant mice is responsive to amphetamine, DAT inhibitor and DA receptor inverse agonist suggesting a specific involvement of striatal DA system. We hypothesize that these ADHD-related phenotype are caused by defects in palmitoylation of one or more DHHC15 substrates in striatum. In this study, we propose to identify dhhc15 in vivo substrates in striatum using functional assays and proteomics, and to characterize the underlying neurobiological mechanisms. Results shall provide valuable insights into a novel regulatory mechanism of DA in striatum and help to identify drug targets for rational development of effective therapies for ADHD.

描述（由申请人提供）：注意力缺陷多动障碍 (ADHD) 是一种常见的精神疾病，全世界学龄儿童的患病率为 3-7%，成人的患病率为 4%。精神稳定剂广泛用于治疗多动症症状，并取得良好的反应。然而，不同的临床效果、对标准治疗方案的无反应和耐受性以及晚年药物滥用和精神疾病风险的增加仍然是严重问题。 ADHD 中纹状体多巴胺 (DA) 系统的失调得到了人类和动物模型的临床、遗传和脑成像研究以及精神兴奋剂的临床有效性的广泛支持。尽管经过了数十年的研究，人们对多动症的精确神经生物学机制仍然知之甚少，这严重阻碍了新型、安全和有效疗法的开发。棕榈酰化是由 DHHC 结构域棕榈酰转移酶家族催化的可逆脂质翻译后修饰。我们培育了一系列 DHHC15 敲除小鼠，它们表现出过度活跃和纹状体 DA 水平降低。突变小鼠的过度活跃对安非他明、DAT 抑制剂和 DA 受体反向激动剂有反应，表明纹状体 DA 系统有特定参与。我们假设这些 ADHD 相关表型是由纹状体中一种或多种 DHHC15 底物的棕榈酰化缺陷引起的。在这项研究中，我们建议使用功能测定和蛋白质组学来鉴定纹状体中的 dhhc15 体内底物，并表征潜在的神经生物学机制。结果将为纹状体中 DA 的新型调节机制提供有价值的见解，并有助于确定药物靶点，以合理开发 ADHD 的有效疗法。