The therapeutic potential of mGlu3 modulation in MeCP2-related disorders

mGlu3 调节在 MeCP2 相关疾病中的治疗潜力

基本信息

批准号：
9189891
负责人：
Branden J Stansley
金额：
$ 5.43万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9189891
关键词：
Address Animal Model Area Astrocytes Autistic Disorder Behavior Behavioral Biology Brain Calcium Cell Culture Techniques Cells Chemosensitization Cognitive Cognitive deficits Communication Cyclic AMP Data Defect Dendritic Spines Development Disease Equilibrium Etiology Exhibits Fragile X Syndrome Freezing Gene Duplication Genes Genetic Glutamates Hippocampus (Brain)Impaired cognition Impairment Knowledge Lead Learning Link Long-Term Depression Measures Mediating Memory Mental Retardation Metabotropic Glutamate Receptors Methyl-CpG-Binding Protein 2 Molecular Mus Muscle hypotonia Mutation Nervous System Physiology Neurodevelopmental Disorder Neuroglia Neurologic Neurons Neuropharmacology Pathology Patients Phenotype Physiology Play Proteins Pyramidal Cells Regulator Genes Research Research Proposals Rett Syndrome Rodent Model Role Second Messenger Systems Seizures Series Signal Transduction Symptoms Synapses Synaptic plasticity Syndrome Systems Biology Testing Therapeutic Training Up-Regulation Vertebral column autism spectrum disorder cognitive function conditioned fear design insight knock-down learning extinction metabotropic glutamate receptor 3 nervous system disorder neuropathology novel overexpression protein expression receptor receptor function response second messenger skills spasticity stereotypy synaptogenesis theories transmission process

项目摘要

Project Summary Precise levels of the gene regulator Methyl CpG Binding Protein 2 (MeCP2) are known to be a key determinant for proper neurological development and function. The importance of balanced levels of MeCP2 is highlighted by the fact that a loss of MECP2 results in an Autism Spectrum Disorder known as Rett Syndrome; in contrast, duplication of MECP2 leads to a disorder known as MECP2 Duplication syndrome. While Rett Syndrome is an extensively well studied disease area, the molecular etiology of MECP2 Duplication Syndrome remains far less understood. This genetic neurodevelopmental disorder has a wide symptomology including stereotypy, hypotonia, severe cognitive impairments, seizures, and autism. Importantly, both of these disorders critically lack effective therapeutic treatment. Therefore, this research proposal has been designed to develop the candidate’s technical research skills that are necessary to conduct independent neuropharmacology research, while having a positive impact on the field of glutamate systems biology and neurological disorders. In rodent models of MECP2 Duplication Syndrome in which MeCP2 is overexpressed, increases in glutamatergic synapse formation in hippocampal neurons occur, as well as impairments in hippocampal synaptic plasticity and cognitive functions in mice. Interestingly, the metabotropic glutamate receptor 3 (mGlu3) has been shown to be involved in regulating synaptic plasticity and cognitive behaviors in mice, and furthermore, mGlu3 expression has been shown to correlate with MeCP2 expression levels in the brain. Therefore, an upregulation of mGlu3 may contribute to neurological impairments seen in MECP2 Duplication rodent models as well as patients. In support of this theory, we present preliminary data indicating significant increases in mGlu3 protein expression in the hippocampus of mice overexpressing MeCP2 as well as impairment in a form of synaptic plasticity known as long-term depression. It is hypothesized that MeCP2-overexpression causes increases in mGlu3 expression and function, which contribute to synaptic plasticity impairments and cognitive deficits observed in learning and memory paradigms. This will be directly tested by measuring mGlu3-induced second messenger signaling as well as mGlu3-mediated synaptic plasticity and cognitive phenotypes in an animal model of MECP2 Duplication syndrome. Taken together, these studies will elucidate new basic biology and physiology of mGlu3, while also identifying the therapeutic potential of mGlu3 modulation for MeCP2-related disorders.

项目摘要基因调节剂甲基CpG结合蛋白2（MECP2）的精确水平已知是关键的确定性用于适当的神经系统发展和功能。平衡水平的MECP2的重要性被突出显示 MECP2的损失导致自闭症谱系障碍称为RETT综合征；相比之下， MECP2的复制导致一种称为MECP2复制综合征的疾病。而Rett综合征是 MECP2复制综合征的分子病因在广泛研究良好的疾病区域，仍然少得多理解。这种遗传神经发育障碍具有广泛的症状，包括刻板印象，低调，严重的认知障碍，癫痫发作和自闭症。重要的是，这两种疾病批判性缺乏有效的治疗治疗。因此，该研究建议旨在开发候选人的技术研究技能是进行独立的神经药理学研究所必需的，同时对谷氨酸系统生物学和神经系统疾病的领域产生积极影响。在啮齿动物中 MECP2复制综合征的模型，其中MECP2过表达，谷氨酸能增加海马神经元中的突触形成以及海马突触可塑性的损伤和小鼠的认知功能。有趣的是，已经显示了代谢性谷氨酸受体3（MGLU3）参与控制小鼠的合成可塑性和认知行为，此外，mglu3 表达已显示与大脑中的MECP2表达水平相关。因此，上调 MGLU3的of可能会导致MECP2复制啮齿动物模型中看到的神经系统障碍以及患者。为了支持该理论，我们提供了初步数据，表明MGLU3蛋白的显着增加在过表达MECP2的小鼠海马中的表达以及突触形式的损伤可塑性称为长期抑郁症。假设MECP2超过表达导致增加 MGLU3表达和功能，这会导致合成可塑性障碍和认知缺陷在学习和记忆范式中观察到。这将通过测量MGLU3诱导的第二个直接测试 Messenger信号传导以及MGLU3介导的合成可塑性和动物的认知表型 MECP2复制综合征的模型。综上所述，这些研究将阐明新的基本生物学和 MGLU3的生理学，同时还鉴定了MGLU3调制对MECP2相关的治疗潜力疾病。