Rheb 1 and mTORC1 Signaling

Rheb 1 和 mTORC1 信号转导

• 批准号: 10171825
• 负责人: PAUL F WORLEY
• 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/10171825
• 关键词: Adaptor Signaling Protein; Amino Acids; Architecture; Behavior; Behavioral; Biochemical; Cells; Cocaine; Cocaine Dependence; Complex; Cytology; Data; Dendrites; Dopamine D1 Receptor; Dopamine Receptor; Drug Addiction; Drug abuse; Electron Microscopy; Endosomes; Event; Excitatory Synapse; Extinction (Psychology); Freezing; Glutamate Receptor; Homeostasis; Image; Interruption; Lysosomes; Mass Spectrum Analysis; Mediating; Methadone; Modeling; Neurons; Nutrient; Pathway interactions; Pharmaceutical Preparations; Phosphoproteins; Phosphorylation; Play; Process; Protein-Serine-Threonine Kinases; Proteins; Receptor Activation; Receptor Inhibition; Receptor Signaling; Regulation; Role; Self Administration; Signal Pathway; Signal Transduction; Site; Surface; Synapses; Testing; Vertebral column; addiction; behavioral plasticity; behavioral response; cell growth; cocaine self-administration; inhibitor/antagonist; metabotropic glutamate receptor type 1; multicatalytic endopeptidase complex; novel strategies; phosphoproteomics; postsynaptic; pressure; prevent; protein degradation; proteostasis; response; sensor; trafficking

Project Summary mTORC1 as an essential signaling pathway for drug addiction. In its canonical role, mTORC1 responds to the energy and nutrient status of cells to control fundamental processes that control cell growth and reestablish homeostasis. mTORC1 is also dynamically activated by cocaine in neurons that express D1 dopamine receptors (D1R) and inhibition of mTORC1 prevents behavioral effects of cocaine including cocaine self- administration. Accordingly, it is important to understand how mTORC1 is activated in neurons and how mTORC1 signaling contributes to effects of cocaine. Aim 1 tests the hypothesis that mTORC1 signaling is induced as part of the homeostatic scaling process that controls the strength of excitatory synapses. Preliminary studies indicate that Rheb1, which is essential for mTORC1 activation, associates with group 1 metabotropic glutamate receptors and endosomes that move synaptic proteins from the postsynaptic spine to sites of protein degradation in the dendrite. Studies will examine trafficking of Rheb1 and test the role of adaptor proteins that may couple Rheb1 to glutamate receptors and play a role in mTORC1 activation. The role of the amino acid sensor GATOR2 will also be examined in mTORC1 activation in neurons. Aim 2 examines the hypothesis that mTORC1 functions as a co-stimulatory pathway for D1R signaling. This hypothesis builds upon use state of the art mass spectroscopic analysis of phosphoproteins to identify signaling crosstalk between mTORC1 and D1R. Studies will also test the hypothesis that persistent activation of mTORC1 can block D1R behaviors by “occluding” D1R signaling. Aim 3 tests the relevance of biochemical signaling pathways in behaviors relevant to cocaine addiction including self-administration and reinstatement after extinction. These studies will define essential mechanisms of mTORC1-D1R signaling important for drug addiction.

项目摘要 mTORC 1是药物成瘾的重要信号通路。在其规范作用中，mTORC 1响应于 细胞的能量和营养状态，以控制控制细胞生长和重建的基本过程 体内平衡。在表达D1多巴胺的神经元中，mTORC 1也被可卡因动态激活 受体（D1 R）和mTORC 1的抑制可防止可卡因的行为效应，包括可卡因自身 局因此，重要的是要了解mTORC 1是如何在神经元中被激活的，以及如何在神经元中被激活。 mTORC 1信号传导有助于可卡因的作用。目的1检验mTORC 1信号传导是 作为控制兴奋性突触强度的稳态缩放过程的一部分而被诱导。 初步研究表明，Rheb 1，这是必不可少的mTORC 1激活，与第1组 代谢型谷氨酸受体和内体，其将突触蛋白从突触后棘移动到 树突中的蛋白质降解位点。研究将检查Rheb 1的贩运，并测试 衔接蛋白，可能耦合Rheb 1谷氨酸受体和发挥作用的mTORC 1激活。的 氨基酸传感器GATOR 2在神经元中mTORC 1激活中的作用也将被检查。目的2 检验了mTORC 1作为D1 R信号传导的共刺激通路发挥作用的假设。这 该假设建立在使用磷蛋白的最新质谱分析来鉴定 mTORC 1和D1 R之间的信号串扰。研究还将检验持续激活 mTORC 1可以通过“阻断”D1 R信号传导来阻断D1 R行为。目标3测试生物化学的相关性 可卡因成瘾相关行为的信号通路，包括自我给药和复吸 在灭绝之后。这些研究将确定mTORC 1-D1 R信号传导的基本机制，对于药物治疗具有重要意义。 成瘾