Rheb 1 and mTORC1 Signaling

Rheb 1 和 mTORC1 信号转导

• 批准号: 10404516
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404516
• 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; 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 MTORC1作为药物成瘾的重要信号通路。在其规范角色中，mTORC1响应 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 动态平衡。可卡因也会动态激活表达D1多巴胺的神经元中的mTORC1 受体(D1R)和抑制mTORC1可阻止包括可卡因自身在内的可卡因的行为效应 行政管理。因此，重要的是要了解mTORC1是如何在神经元中被激活的，以及如何 MTORC1信号转导参与可卡因的作用。AIM 1测试了假设mTORC1信号是 作为控制兴奋性突触强度的稳态伸缩过程的一部分而诱导。 初步研究表明，对mTORC1激活至关重要的Rheb1与组1有关 代谢性谷氨酸受体和内小体将突触蛋白从突触后棘移到 树突中蛋白质降解的部位。研究将检查Rheb1的贩运情况，并测试 可能将Rheb1偶联到谷氨酸受体并在mTORC1激活中发挥作用的接头蛋白。这个 氨基酸传感器GATOR2在神经元mTORC1激活中的作用也将得到检验。目标2 检验了mTORC1作为D1R信号的共刺激途径的假设。这 假说建立在使用最先进的磷蛋白质谱分析来识别 MTORC1和D1R之间的信号串扰。研究还将检验持续激活的假说 可通过“阻断”D1R信号来阻断D1R行为。目标3测试生物化学的相关性 与可卡因成瘾相关的行为中的信号通路，包括自我管理和恢复 在灭绝之后。这些研究将确定mTORC1-D1R信号对药物的重要作用的基本机制 上瘾。