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.

项目概要已知基因调节剂甲基 CpG 结合蛋白 2 (MeCP2) 的精确水平是关键决定因素强调了 MeCP2 平衡水平的重要性。相反，MECP2 缺失会导致自闭症谱系障碍（称为雷特综合症）； MECP2 重复会导致一种称为 MECP2 重复综合征的疾病，而雷特综合征是一种疾病。在疾病领域，MECP2 重复综合征的分子病因学得到了广泛的研究，但仍知之甚少。这种遗传性神经发育障碍具有广泛的症状，包括刻板印象、肌张力低下、严重认知障碍、癫痫发作和自闭症，这两种疾病都很严重。因此，本研究旨在开发有效的治疗方法。候选人进行独立神经药理学研究所需的技术研究技能，同时对谷氨酸系统生物学和神经系统疾病领域产生积极影响。 MECP2 重复综合征模型，其中 MeCP2 过度表达，谷氨酸能增加海马神经元中发生突触形成，以及海马突触可塑性受损代谢型谷氨酸受体 3 (mGlu3) 已显示出对小鼠认知功能的影响。参与调节小鼠的突触可塑性和认知行为，此外，mGlu3 研究表明，MeCP2 的表达与大脑中 MeCP2 的表达水平相关。 mGlu3 可能会导致 MECP2 重复啮齿动物模型以及为了支持这一理论，我们提供了表明 mGlu3 蛋白显着增加的初步数据。过度表达 MeCP2 的小鼠海马体中的表达以及突触形式的损伤人们重新认识到，MeCP2 过度表达会导致长期抑郁症的可塑性增加。 mGlu3 表达和功能，导致突触可塑性损伤和认知缺陷这将通过测量 mGlu3 诱导的第二次直接测试。动物中的信使信号传导以及 mGlu3 介导的突触可塑性和认知表型 MECP2 重复综合征模型总而言之，这些研究将阐明新的基础生物学和 mGlu3 的生理学，同时还确定了 mGlu3 调节对 MeCP2 相关的治疗潜力失调。