Thorase Regulation of the Actions of Cocaine

Thorase 对可卡因作用的调节

基本信息

批准号：
10171826
负责人：
VALINA L. DAWSON
金额：
$ 37.67万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171826
关键词：
AMPA Receptors ATP phosphohydrolase Addictive Behavior Address Affect Affinity Chromatography Behavior Behavioral Binding Biochemical Brain Cocaine Cocaine Dependence Cocaine Users Collaborations Complex Data Drug abuse Event Exposure to Extinction (Psychology)FRAP1 gene Genetic Genetically Engineered Mouse Goals Health Investigation Lead Learning Lysosomes Maintenance Maps Mediating Membrane Memory Metabolism Mitochondria Monitor Morphology Motor Mus Neuronal Plasticity Play Property Proteins Proteome Proteomics Public Health RNA Regulation Respiration Ribosomes Rodent Role Self Administration Set protein Signal Pathway Signal Transduction Sirolimus Stress Surface Synapses Synaptic plasticity Tail Technology Translating Translations addiction cocaine exposure drug of abuse insight novel strategies novel therapeutics preservation protein complex receptor expression response transcriptome transcriptome sequencing translatome

项目摘要

Thorase Regulation of the Actions of Cocaine Addiction to drugs of abuse such as cocaine is a world-wide health crisis. In the USA there are an estimated 1.5 million current cocaine users, a number that has been relatively stable. Extensive studies have revealed that cocaine, induces plastic changes in the brain that underlie the behavioral changes including changes in expression of AMPA receptors as well as activation of the mechanistic target of rapamycin complex 1 (mTORC1) in the onset and maintenance of cocaine addiction. We discovered Thorase, an AAA+ ATPases that serves to facilitate the disassembly AMPA receptors and recently discovered it also disassembles mTORC1. Our hypothesis is that Thorase is poised to play a pivotal and critical role in the behavioral and cellular responses to cocaine by directing both AMPA receptor expression and mTORC1 activity and thus underlies important changes in dopaminergic neuroplasticity which we will explore in the following Aims. Aim 1: In order to fully comprehend the actions of cocaine on Thorase and mTOR signaling the functional and biochemical interactions of Thorase with mTOR and components of mTORC1 will be explored and defined. Aim 2: The role of Thorase activity on cocaine’s reinforcing properties will be studied. Self-administration and reinstatement to cocaine seeking behavior will be monitored in wild type, Thorase KO and Thorase TG mice. Aim 3: As Rapamycin blocks cocaine induced behaviors in rodents, it is reasonable to predict that cocaine is hyperactivating mTORC1. Since inhibition or genetic deletion of nNOS, and thus NO, has similar effects on cocaine behaviors as rapamycin, and S-nitrosylation inhibits Thorase activity, we hypothesize that cocaine is inhibiting Thorase through S-nitrosylation resulting in hyperactivation of mTORC1 and altering expression of AMPA receptors. Aim 4: Will address whether mTORC1 and Thorase are largely responsible for the proteomic and translational changes following exposure to cocaine. Changes to the transcriptome, translatome and proteome in response to cocaine exposure will be explored. The overarching goal of this project is to define the role of Thorase in the regulation of neuroplastic responses that underlie the addictive behaviors to cocaine.

可卡因作用的胸酶调节对可卡因等滥用药物的成瘾是世界范围内的健康危机。在美国有一个估计当前可卡因用户有150万，这个数字相对稳定。广泛的研究揭示可卡因会引起大脑的塑性变化，这是行为变化的基础 AMPA接收器表达的变化以及雷帕霉素机械靶标的激活在可卡因成瘾的发作和维持中，复杂的1（mTORC1）。我们发现了Thorase，AAA+ ATPases有助于促进拆卸AMPA接收器，并且最近也发现了分解MTORC1。我们的假设是，胸他在通过指导AMPA受体表达和MTORC1，行为和细胞对可卡因的反应活动，因此是多巴胺能神经塑性的重要变化的基础，我们将在以下目标。目标1：为了完全理解可卡因对胸酶和mTOR信号的作用将探索Thorase与MTOR和MTORC1组成部分的生化相互作用，并将被探索定义。 AIM 2：胸腔活动在可卡因增强特性中的作用将是研究的。自我管理和将恢复到可卡因行为的恢复原状将在野生型，胸酶KO和Thorase TG小鼠中进行监测。目的3：当雷帕霉素阻断啮齿动物中可卡因诱导的行为时，可以合理地预测可卡因是过度活化的mTORC1。由于NNO的抑制或遗传缺失，因此没有，对可卡因行为是雷帕霉素，S-亚硝基化抑制了胸酶的活性，我们假设可卡因是通过S-亚硝基化抑制胸酶，导致MTORC1过度激活并改变了表达 AMPA接收器。目标4：将解决MTORC1和Thrase是否在很大程度上负责蛋白质组学和暴露于可卡因后的翻译变化。更改转录组，翻译组和将探讨蛋白质组对可卡因暴露的响应。该项目的总体目标是定义胸腔在调节神经塑性中的作用构成可卡因的添加剂行为的反应。