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Metabotropic Glutamate Receptor 7 as a Novel Therapeutic Target for MECP2 Duplication Syndrome

代谢型谷氨酸受体 7 作为 MECP2 重复综合征的新治疗靶点

基本信息

批准号：
9466186
负责人：
Nicole Marie Fisher
金额：
$ 2.87万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2020-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9466186
关键词：
Affect Age Animals Apnea Autopsy Back Behavior Brain Brain region Cerebellum Chemosensitization Child Cognition Cognitive Corpus striatum structure Data Diagnosis Disease Electrophysiology (science)Excitatory Postsynaptic Potentials Exhibits Extinction (Psychology)Female Freezing Fright G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Gene Dosage Gene Expression Genes Glutamates Hippocampus (Brain)Impairment In Vitro Intellectual functioning disability Lead Learning Long-Term Potentiation Memory Memory impairment Methyl-CpG-Binding Protein 2 Modeling Mus Neurobehavioral Manifestations Neurodevelopmental Disorder Neurologic Neurons Patients Pharmacological Treatment Pharmacology Phenotype Presynaptic Terminals Receptor Activation Reporting Research Proposals Rett Syndrome Reversal Learning Role Sampling Seizures Slice Speech Synapses Synaptic plasticity Syndrome Testing Therapeutic Translating Western Blotting behavior test conditioned fear fear memory hippocampal pyramidal neuron insight learned behavior loss of function loss of function mutation metabotropic glutamate receptor 7 morris water maze motor control motor impairment mouse model nervous system disorder neurophysiology neurotransmitter release new therapeutic target novel therapeutic intervention overexpression positive allosteric modulator postsynaptic protein expression receptor respiratory response skills spatial memory tool transcription factor

项目摘要

PROJECT SUMMARY Loss-of-function mutation of the Methyl CpG Binding Protein 2 (MECP2) gene causes a severe neurodevelopmental disorder known as Rett syndrome (RTT), while duplication of its locus leads to MECP2 Duplication syndrome (MDS). Children with each diagnosis can present with profound intellectual disability for which there is currently no treatment. Here we provide preliminary data showing that expression of the metabotropic glutamate receptor 7 (mGlu7), a receptor with known roles in synaptic plasticity and cognition, is altered downstream of changes in MECP2 gene dosage. While potentiation of mGlu7 activity ameliorates phenotypes in RTT mice, the therapeutic potential of mGlu7 modulation in a model of MDS remains unexplored. Completion of this research proposal will thoroughly investigate the efficacy of mGlu7 modulation in paradigms of learning and memory in a mouse model of MDS and provide new mechanistic insight into the neurophysiological role of mGlu7 in the context of MeCP2-related disorders.

项目摘要甲基CpG结合蛋白2（MECP2）基因的功能缺失突变导致严重的神经发育障碍称为Rett综合征（RTT），而其位点的重复导致 MECP2复制综合征（MDS）。每种诊断的儿童都可能表现出深刻的目前没有治疗方法的智力残疾。在这里我们提供初步数据显示代谢型谷氨酸受体7（mGlu7）的表达，在突触可塑性和认知中的作用，在MECP 2基因的变化下游被改变，剂量.虽然mGlu7活性的增强改善了RTT小鼠的表型，但治疗性药物 MDS模型中mGlu7调节的潜力仍未探索。完成本一项研究计划将彻底调查mGlu7调节在以下范例中的功效：在MDS小鼠模型中的学习和记忆，并提供了新的机制洞察， mGlu7在MeCP2相关疾病背景下的神经生理学作用。