Mechanism of Gp1 mGluR-dependent translation and plasticity

Gp1 mGluR 依赖性翻译和可塑性机制

基本信息

批准号：
10094921
负责人：
Nien-Pei Tsai
金额：
$ 37.77万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10094921
关键词：
Animal Behavior Animal Model Animals Brain Cancer Biology Cell Nucleus Cells Clinical Trials Cognition Cytoplasm Data Development Disease Double Minutes Environment FMR1 Fragile X Syndrome Genes Genets Hippocampus (Brain)Human Impairment Inherited Intention Knock-out Knockout Mice Knowledge Lead Long-Term Depression Mediating Mental disorders Microfluidic Microchips Molecular Mus Nervous system structure Neuronal Plasticity Neurons Organism Outcome Patients Pharmacology Phenotype Physiological Polyribosomes Process Proteins Publishing Receptor Activation Receptor Signaling Repression Research Ribosomal Proteins Ribosomes Role Study models Synapses Synaptic Transmission Synaptic plasticity Translational Activation Translational Repression Translations autism spectrum disorder base experience in vivo knock-down loss of function mutation metabotropic glutamate receptor 5 metabotropic glutamate receptor type 1 mouse model nervous system disorder new therapeutic target novel optogenetics protein activation synaptic depression ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY/ABSTRACT Adaptation of living organisms to constantly changing environments depends on the plasticity of the nervous system. Neuronal plasticity often requires activity-dependent translation to rapidly supply selected proteins, for example, through activation of Group 1 metabotropic glutamate receptors (Gp1 mGluRs). Gp1 mGluRs, including mGluR1 and mGluR5, mediate translation-dependent synaptic plasticity, including long-term synaptic depression (LTD). Dysregulated Gp1 mGluR signaling is observed with various neurological and mental disorders, including Fragile X Syndrome (FXS) and autism spectrum disorders (ASDs). Although pharmacological correction of Gp1 mGluR activity reverses many of the phenotypes in animal models of those diseases, the molecular and cellular mechanisms underlying Gp1 mGluR-mediated synaptic plasticity have been elusive. Our published and preliminary data introduce the ubiquitin E3 ligase Murine double minute-2 (Mdm2) as a novel translational repressor and a “switch” that permits Gp1 mGluR-induced protein translation (Liu et al., Hum Mol Genet., 2017). In our proposed research, we aim to characterize the role of Mdm2 in Gp1 mGluR- dependent synaptic plasticity (Aim 1) and determine the mechanism by which Mdm2 mediates activity-dependent protein translation (Aim 2). Our new data also show that Mdm2 is molecularly altered and unresponsive to Gp1 mGluR activation in the Fmr1 knockout (KO) mouse, the commonly used animal model for studying FXS (Tsai et al., Hum Mol Genet., 2017). In Aim 3 we will characterize the mechanism by which Fmr1 interconnects Gp1 mGluR signaling to permit translational activation through de-repressing Mdm2. Successful completion of this proposal will greatly facilitate the understanding of Gp1 mGluR-mediated synaptic plasticity through a novel mechanism of translational control. Building on the deep knowledge of Mdm2 in cancer biology, our research will also open a new avenue for the study of neurological disorders associated with abnormal Gp1 mGluR signaling.

项目概要/摘要生物体对不断变化的环境的适应取决于生物体的可塑性神经系统的可塑性通常需要依赖于活动的翻译来快速提供选定的信息。例如，通过激活第 1 组代谢型谷氨酸受体 (Gp1 mGluR)。 mGluR，包括 mGluR1 和 mGluR5，介导翻译依赖性突触可塑性，包括长期突触可塑性突触抑制 (LTD) 在各种神经和精神疾病中均观察到 Gp1 mGluR 信号传导失调。疾病，包括脆性 X 综合征 (FXS) 和自闭症谱系障碍 (ASD)。 Gp1 mGluR 活性的药理学校正可逆转这些动物模型中的许多表型疾病，Gp1 mGluR 介导的突触可塑性的分子和细胞机制已被研究我们已发表的初步数据介绍了泛素 E3 连接酶鼠双分钟-2 (Mdm2)。一种新型翻译抑制因子和一个“开关”，允许 Gp1 mGluR 诱导的蛋白质翻译（Liu 等人， Hum Mol Genet., 2017）在我们提出的研究中，我们的目标是描述 Mdm2 在 Gp1 mGluR- 中的作用。依赖性突触可塑性（目标 1）并确定 Mdm2 介导活动依赖性的机制蛋白质翻译（目标 2）。我们的新数据还表明 Mdm2 发生了分子改变并且对 Gp1 无反应。 Fmr1 敲除 (KO) 小鼠中的 mGluR 激活，Fmr1 敲除 (KO) 小鼠是研究 FXS 的常用动物模型 (Tsai 等人，Hum Mol Genet.，2017）在目标 3 中，我们将描述 Fmr1 互连 Gp1 的机制。 mGluR 信号通过去抑制 Mdm2 来允许翻译激活成功完成此任务。该提案将通过一种新颖的方法极大地促进对 Gp1 mGluR 介导的突触可塑性的理解基于对 Mdm2 在癌症生物学方面的深入了解，我们的研究还将为研究与异常 Gp1 mGluR 相关的神经系统疾病开辟新途径发信号。