Rheb 1 and mTORC1 Signaling

Rheb 1 和 mTORC1 信号转导

基本信息

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
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/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

项目摘要

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.

项目概要 mTORC1 作为药物成瘾的重要信号通路在其典型作用中，mTORC1 对药物成瘾作出反应。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表达 D1 多巴胺的神经元中的 mTORC1 也会被可卡因动态激活。受体（D1R）和 mTORC1 的抑制可防止可卡因的行为影响，包括可卡因自身因此，了解 mTORC1 在神经元中如何被激活以及如何被激活非常重要。 mTORC1 信号传导有助于可卡因的作用目标 1 检验 mTORC1 信号传导的假设。作为控制兴奋性突触强度的稳态缩放过程的一部分而引起。初步研究表明，对于 mTORC1 激活至关重要的 Rheb1 与组 1 相关代谢型谷氨酸受体和内体将突触蛋白从突触后棘移动到研究将检查 Rheb1 的运输并测试其作用。接头蛋白可将 Rheb1 与谷氨酸受体偶联并在 mTORC1 激活中发挥作用。 Aim 2 还将检查氨基酸传感器 GATOR2 在神经元 mTORC1 激活中的作用。检查 mTORC1 作为 D1R 信号传导的共刺激途径的假设。该假设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设。 mTORC1 可以通过“阻断”D1R 信号传导来阻断 D1R 行为 Aim 3 测试生化的相关性。与可卡因成瘾相关的行为信号通路，包括自我给药和恢复这些研究将确定对药物很重要的 mTORC1-D1R 信号传导的基本机制。瘾。