DHHC 15 palmitoylation modulates striatal dopamine system

DHHC 15 棕榈酰化调节纹状体多巴胺系统

• 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
• 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

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）：注意缺陷多动障碍（ADHD）是一种常见的精神疾病，全世界学龄儿童患病率为3- 7%，成人患病率为4%。精神药物被广泛用于治疗ADHD症状，并有良好的反应。然而，不同的临床疗效，对标准治疗方案的无反应性和耐受性，以及在以后的生活中滥用药物和精神疾病的风险增加仍然是严重的问题。注意缺陷多动障碍患者纹状体多巴胺（DA）系统的失调已被临床、遗传、人类和动物模型的脑成像研究以及精神兴奋剂的临床效果广泛支持。尽管经过几十年的研究，ADHD的确切神经生物学机制仍然知之甚少，这严重阻碍了新型、安全、有效治疗方法的发展。棕榈酰化是一种可逆的脂质翻译后修饰，由dhhc结构域棕榈酰转移酶家族催化。我们培育了一组dhhc15基因敲除小鼠，这些小鼠在纹状体中表现出过度活跃和DA水平降低。突变小鼠的多动症对安非他明、DAT抑制剂和DA受体逆激动剂有反应，提示纹状体DA系统特异性参与。我们假设这些adhd相关表型是由纹状体中一种或多种DHHC15底物棕榈酰化缺陷引起的。在这项研究中，我们建议使用功能分析和蛋白质组学来鉴定纹状体中dhhc15的体内底物，并表征其潜在的神经生物学机制。研究结果将为纹状体中DA的新调控机制提供有价值的见解，并有助于确定药物靶点，以合理开发有效的ADHD治疗方法。