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Role of MeCP2 in Circuitry Development and Plasticity

MeCP2 在电路发育和可塑性中的作用

基本信息

批准号：
8758660
负责人：
Qizhi Gong
金额：
$ 32.29万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8758660
关键词：
Adult Alleles Antibodies Apical Axon Behavior Binding Biological Models Brain Candidate Disease Gene Cell Adhesion Molecules Characteristics Cognitive CpG Islands CpG dinucleotide DNA Binding Defect Dendrites Development Etiology Future Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genomics Goals Health Internal Ribosome Entry Site Knockout Mice Knowledge Label Lentivirus Vector Mediating Methyl-CpG-Binding Protein 2 Modeling Morphology Mus Mutation Nasal cavity Nervous system structure Neuraxis Neurodevelopmental Disorder Neuronal Plasticity Neurons Odorant Receptors Olfactory Epithelium Olfactory Pathways Phenotype Phosphorylation Physiological Play Population Presynaptic Terminals Process Receptor Gene Regulation Rett Syndrome Reverse Transcriptase Polymerase Chain Reaction Role Site Testing Tissues Transcriptional Regulation cell type chromatin immunoprecipitation density differential expression gene function insight knockout gene lentiviral-mediated mitral cell mouse genome olfactory bulb olfactory sensory neurons postnatal presynaptic promoter receptor expression research study synaptogenesis therapeutic development therapy design

项目摘要

DESCRIPTION (provided by applicant): Rett syndrome is a neurodevelopmental disorder caused by mutations in the methyl CpG binding protein 2 gene (Mecp2). Loss of Mecp2 function results in defects in neuronal maturation, synaptogenesis and dendritic development in the central nervous system. MeCP2 is a transcription regulator that binds preferentially to methylated CpG dinucleotides sequences. Identification of MeCP2 target genes and understanding their functions in the establishment of functional circuitry is critical for future development of therapeutic approaches. Several unique characteristics make the vertebrate olfactory system an excellent model to study MeCP2 function. 1). Olfactory sensory neurons are the sole neuronal type in the olfactory epithelium. This will facilitate the identification of transcription regulations without the interference of mixed regulatory effects that are seen in mixed neuronal populations of cortical tissue. 2) The intricate and precise olfactory connections allow identification of axon mistargeting out of their specific olfactory bulb foci. 3) Manipulation of neuronal activity at the physiological level can be easily achieved due to the accessibility of olfactory sensory neurons in the nasal cavity. The goal of this study is to use the olfactory system as a model to further define MeCP2 function in circuitry formation and refinement. In Aim 1, we will test the hypothesis that MeCP2 is required for the formation of precise adult olfactory connections. In Aim 2, we will test the hypothesis that MeCP2 regulates expression of cell adhesion molecules in olfactory sensory neurons. In Aim 3, we will test the hypothesis that MeCP2 tunes transcription of activity-regulated cell adhesion molecules in the olfactory system. Through this study, we hope to gain better understanding of MeCP2 function not only in the olfactory system but also in other regions of the central nervous system.

描述（由申请人提供）：Rett综合征是一种由甲基CpG结合蛋白2基因（Mecp2）突变引起的神经发育障碍。Mecp2功能的丧失导致中枢神经系统中神经元成熟、突触发生和树突发育的缺陷。MeCP2是优先结合甲基化CpG二核苷酸序列的转录调节因子。鉴定MeCP2靶基因并了解其在建立功能电路中的功能对于未来开发治疗方法至关重要。几个独特的特性使脊椎动物嗅觉系统的一个很好的模型，研究MeCP2功能。1）。嗅感觉神经元是嗅上皮中唯一的神经元类型。这将有助于识别转录调节，而不会干扰混合调节效应，这在皮层组织的混合神经元群体中可见。2)复杂而精确的嗅觉连接允许识别出其特定嗅球病灶的轴突错误定位。3)由于鼻腔中嗅觉感觉神经元的可接近性，可以容易地实现在生理水平上对神经元活动的操纵。本研究的目的是使用嗅觉系统作为模型，以进一步定义MeCP2在回路形成和细化中的功能。在目标1中，我们将测试MeCP2是形成精确的成人嗅觉连接所必需的假设。在目标2中，我们将检验MeCP 2调节嗅觉感觉神经元中细胞粘附分子表达的假设。在目标3中，我们将测试的假设，MeCP2调谐活性调节细胞粘附分子在嗅觉系统中的转录。通过这项研究，我们希望更好地了解MeCP 2不仅在嗅觉系统中，而且在中枢神经系统的其他区域中的功能。