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：
10516050
负责人：
Nien-Pei Tsai
金额：
$ 37.66万
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/10516050
关键词：
Animal Behavior Animal Model Brain Cancer Biology Cell Cycle Cell Nucleus Clinical Trials Cognition Cytoplasm Data Development Disease Double Minutes Environment FMR1 Fragile X Syndrome Genes Genets Hippocampus Human Impairment Inherited Intention Knock-out Knockout Mice Knowledge Lead Long-Term Depression Mediating Mental disorders Microfluidic Microchips Molecular Mus Nervous System Neuronal Differentiation Neuronal Plasticity Neurons Organism Outcome Patients Phenotype Physiological Polyribosomes Process Proteins Publishing Receptor Activation Receptor Signaling Research Ribosomal Proteins Ribosomes Role Study models Synapses Synaptic Transmission Synaptic plasticity Translational Activation Translational Repression Translations autism spectrum disorder derepression 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 pharmacologic protein activation synaptic depression ubiquitin-protein ligase

Animal Behavior Animal Model Brain Cancer Biology Cell Cycle Cell Nucleus Clinical Trials Cognition Cytoplasm Data Development Disease Double Minutes Environment FMR1 Fragile X Syndrome Genes Genets Hippocampus Human Impairment Inherited Intention Knock-out Knockout Mice Knowledge Lead Long-Term Depression Mediating Mental disorders Microfluidic Microchips Molecular Mus Nervous System Neuronal Differentiation Neuronal Plasticity Neurons Organism Outcome Patients Phenotype Physiological Polyribosomes Process Proteins Publishing Receptor Activation Receptor Signaling Research Ribosomal Proteins Ribosomes Role Study models Synapses Synaptic Transmission Synaptic plasticity Translational Activation Translational Repression Translations autism spectrum disorder derepression 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 pharmacologic protein activation synaptic depression ubiquitin-protein ligase

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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.