The Role of Ubiquitination in Methamphetamine Neurotoxicity (CDA)

泛素化在甲基苯丙胺神经毒性 (CDA) 中的作用

• 批准号: 8314099
• 负责人: Anna Moszczynska
• 金额: $ 24.15万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314099
• 关键词: 26S proteasome; Accident and Emergency department; Affect; Animal Model; Antidotes; Autoreceptors; Binding; Cell Death; Cell membrane; Cell physiology; Characteristics; Cytosol; DNA; Data; Development; Dopamine; Dopamine D2 Receptor; Dose; Drug toxicity; Electron Transport; Electrons; Energy Metabolism; Enzymes; Exocytosis; Filament; Goals; Impaired cognition; Impairment; Intervention; Knowledge; Lead; Learning; Life; Link; Lipids; Mediating; Membrane; Mentors; Methamphetamine; Methamphetamine dependence; Mitochondria; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Overdose; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physicians; Play; Process; Production; Property; Proteins; Reactive Oxygen Species; Receptor Signaling; Recycling; Regulation; Research; Research Personnel; Role; Signal Transduction; Site; Solid; Synapses; Synaptic Vesicles; System; Techniques; Testing; Toxic Actions; Toxic effect; Toxin; Transcriptional Regulation; Transmembrane Transport; Travel; Ubiquitin; Ubiquitination; Up-Regulation; Vesicle; Work; base; career; dopamine transporter; dopaminergic neuron; experience; feeding; genetic regulatory protein; in vivo; methamphetamine abuse; mitochondrial dysfunction; multicatalytic endopeptidase complex; neuroprotection; neurotoxicity; neurotransmission; novel; overexpression; oxidation; oxidative damage; parkin gene/protein; prevent; programs; protein misfolding; protein protein interaction; receptor; receptor expression; receptor function; restoration; skills; stressor; trafficking; ubiquitin-protein ligase; uptake; vesicular monoamine transporter; vesicular monoamine transporter 2

DESCRIPTION (provided by applicant): My long-term academic career goal is to conduct independent research into the discovery of new molecular pathways involved in toxicity of drugs that affect dopaminergic system, particularly methamphetamine (MA), in order to develop better treatments for their abusers. Ubiquitination is emerging as a multifunctional signal in cellular processes; therefore, it is a potential novel signal in MA neurotoxicity. There is no data on the role of ubiquitination after high-dose MA; therefore, my immediate goal is to investigate the involvement of ubiquitination-mediating E3 ligases (particularly parkin) in regulation of proteins known to be affected by MA toxic actions, and vice versa, namely ubiquitin proteasomal system, mitochondrial electron chain proteins, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2), in animal model of MA toxicity. Since parkin protects against a variety of cellular stressors, including agents affecting mitochondrial function, it is planned to determine whether parkin (or other E3 ligases) protects dopaminergic neurons against MA in vivo. The specific aims are: (1) to examine the effect of parkin on MA neurotoxicity, (2) to investigate the effect of MA on parkin function and the catalytic properties of the proteasome, (2) to investigate the interactions between decreased parkin function and mitochondrial electron transport chain activity, (3) (4) to investigate ubiquitination-mediated DAT trafficking after MA, and (5) to determine the molecular link between the DAT, parkin and VMAT2 after MA. The proposed mentored research will allow me to develop skills needed for independent career and to learn new techniques, particularly to acquire solid experience working with animal model of MA toxicity. Such knowledge and experience will help me with my independent studies directed toward the identification of new targets that may hopefully drive the development of novel drugs that can treat or prevent neurodegeneration caused by MA. Since factors involved in neurotoxicity interact with each other, it is very important to understand their interactions in order to elucidate points for pharmaceutical intervention. To date, there are no safe and tested medications for treating MA addiction and new MA antidotes for use by emergency room physicians to treat MA-related overdoses are needed. The results from my studies will assist the development of pharmacological therapies to ameliorate potential neuronal damage and cognitive impairments due to MA abuse.

描述（由申请人提供）：我的长期学术职业目标是对发现与影响多巴胺能系统（尤其是甲基苯丙胺）（MA）的药物毒性的新分子途径进行独立研究，以便为其施虐者开发更好的治疗方法。在细胞过程中，泛素化成为一种多功能信号。因此，它是MA神经毒性中潜在的新型信号。没有关于高剂量MA后泛素化作用的数据；因此，我的近期目标是调查泛素化中的E3连接酶（尤其是帕克蛋白）在调节已知受MA有毒作用影响的蛋白质中，反之亦然，反之亦然，即泛素蛋白酶体系统，即线粒体链蛋白，多巴胺型2（detporter）2（vesimort）2（vesimort）2（vesimort）（vesimort）（vesimort）（vesimort）（vesimort）（vesimort）（vesimort）。 MA毒性。由于Parkin可以预防各种细胞应激源，包括影响线粒体功能的药物，因此计划确定Parkin（或其他E3连接酶）是否可以保护多巴胺能神经元免受体内MA的影响。 The specific aims are: (1) to examine the effect of parkin on MA neurotoxicity, (2) to investigate the effect of MA on parkin function and the catalytic properties of the proteasome, (2) to investigate the interactions between decreased parkin function and mitochondrial electron transport chain activity, (3) (4) to investigate ubiquitination-mediated DAT trafficking after MA, and (5) to determine the molecular link between the DAT, parkin和MA之后的VMAT2。拟议的指导研究将使我能够发展独立职业所需的技能并学习新技术，尤其是获得与MA毒性动物模型一起工作的扎实经验。这种知识和经验将帮助我进行我的独立研究，这些研究针对新靶标，这些研究可能希望推动可以治疗或预防MA引起的神经变性的新型药物的开发。由于涉及神经毒性的因素相互相互作用，因此了解其相互作用以阐明药物干预点非常重要。迄今为止，不需要安全且经过测试的药物来治疗MA成瘾和新的MA解毒剂，供急诊室医生使用以治疗与MA相关的过量药物。我的研究结果将有助于开发药理学疗法，以改善由于MA滥用而导致的潜在神经元损害和认知障碍。