Thorase Regulation of the Actions of Cocaine

Thorase 对可卡因作用的调节

• 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
• 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

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.

辅酶作用的酶调节 对可卡因等滥用药物上瘾是一个世界性的健康危机。在美国，有一个 估计目前有150万可卡因使用者，这一数字相对稳定。了大量的研究 研究表明，可卡因会引起大脑的可塑性变化，这些变化是行为变化的基础， AMPA受体表达的变化以及雷帕霉素机制靶点的激活 复合物1（mTORC 1）在可卡因成瘾的发作和维持中的作用。我们发现了Thorase，AAA+ 用于促进AMPA受体分解的ATP酶，最近发现它也 拆解mTORC 1。我们的假设是，Thorase准备发挥关键和关键的作用， 通过指导AMPA受体表达和mTORC 1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的重要变化的基础，我们将在 遵循目标。 目的1：为了全面了解可卡因对Thorase和mTOR信号通路的作用， 将探索Thorase与mTOR和mTORC 1组分的生物化学相互作用， 定义了 目的2：研究Thorase活性对可卡因强化作用的影响。自我施用和 将在野生型、Thorase KO和Thorase TG小鼠中监测可卡因寻求行为的恢复。 目的3：由于雷帕霉素可以阻断可卡因诱导的啮齿动物行为，因此可以合理预测可卡因对啮齿动物的作用 过度激活mTORC 1。由于nNOS的抑制或基因缺失以及因此NO的抑制或基因缺失对细胞增殖具有类似的作用， 可卡因的行为与雷帕霉素相似，S-亚硝基化抑制Thorase活性，我们假设可卡因是 通过S-亚硝基化抑制Thorase，导致mTORC 1的过度活化，并改变 AMPA受体。 目的4：将解决mTORC 1和Thorase是否主要负责蛋白质组学， 在接触可卡因后的转化变化。转录组、翻译组和 蛋白质组对可卡因暴露的反应将被探索。 该项目的首要目标是确定Thorase在神经可塑性调节中的作用。 对可卡因成瘾行为的反应。