Thorase Regulation of the Actions of Cocaine

Thorase 对可卡因作用的调节

基本信息

批准号：
10404517
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10404517
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.

Thorase 对可卡因作用的调节可卡因等滥用药物成瘾是一场世界范围的健康危机。据估计，目前有 150 万可卡因使用者，这一数字相对稳定。研究表明，可卡因会引起大脑的可塑性变化，从而导致行为变化，包括 AMPA 受体表达的变化以及雷帕霉素机制靶点的激活复合体 1 (mTORC1) 在可卡因成瘾的发作和维持中的作用我们发现了 Thorase，一种 AAA+ 的药物。 ATP酶有助于促进AMPA受体的分解，最近还发现了它我们的假设是 Thorase 有望在该过程中发挥关键作用。通过指导 AMPA 受体表达和 mTORC1 来调节对可卡因的行为和细胞反应活动，因此是多巴胺能神经可塑性重要变化的基础，我们将在遵循目标。目标 1：为了充分理解可卡因对 Thorase 和 mTOR 信号传导功能的作用将探索 Thorase 与 mTOR 和 mTORC1 成分的生化相互作用定义的。目标 2：将研究 Thorase 活性对可卡因增强特性的作用。将监测野生型、Thorase KO 和 Thorase TG 小鼠恢复可卡因寻求行为的情况。目标 3：由于雷帕霉素可阻断啮齿动物中可卡因诱导的行为，因此可以合理地预测可卡因由于 nNOS 的抑制或基因缺失，以及 NO，对 mTORC1 具有类似的作用。可卡因的行为与雷帕霉素相同，并且 S-亚硝基化会抑制 Thorase 活性，我们发现可卡因是通过 S-亚硝基化抑制 Thorase，导致 mTORC1 过度激活并改变 AMPA 受体。目标 4：将解决 mTORC1 和 Thorase 是否主要负责蛋白质组和接触可卡因后转录组、翻译组和转录组的变化。将探索对可卡因暴露作出反应的蛋白质组。该项目的总体目标是确定 Thorase 在神经可塑性调节中的作用可卡因成瘾行为背后的反应。