Understanding the Pathogenic Mechanisms of Rett Syndrome

了解雷特综合征的发病机制

基本信息

批准号：
8850004
负责人：
Zhaolan Zhou
金额：
$ 34.33万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850004
关键词：
Address Autistic Disorder Award Basic Science Behavioral Binding Binding Sites Biological Neural Networks Biological Process Brain Brain region Cells Clinical Clinical Research Cognitive deficits Communities Corpus striatum structure Cre-LoxP DNA DNA Binding DNA Methylation Data Defect Development Diagnosis Disease Epigenetic Process Etiology Event-Related Potentials Foundations Functional disorder Funding Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Health Human Impairment In Vitro Intellectual functioning disability International Interneurons Knockout Mice Lead Link Maps Mediating Mental Depression Methyl-CpG-Binding Protein 2 Missense Mutation Molecular Mus Mutation Neurons Outcome Parvalbumins Pathogenesis Pathway interactions Patients Pattern Pennsylvania Pharmaceutical Preparations Phenotype Play Population Prosencephalon Proteins Reader Research Research Project Grants Resolution Resources Rett Syndrome Role Schizophrenia Series Somatostatin Specific qualifier value Structure Symptoms System Therapeutic Time Transgenic Organisms Translations United States National Institutes of Health Universities Work age related autism spectrum disorder base behavioral genomics biochip cell type epigenomics genome-wide girls in vivo information processing innovation insight loss of function methylome motor disorder mouse model mutant mouse model nervous system disorder neural circuit neuronal circuitry neurophysiology neuropsychiatry novel novel therapeutics research study response tool transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause the autism spectrum disorder Rett Syndrome (RTT). To understand the pathogenesis of RTT, we previously developed and characterized a mouse model recapitulating an RTT-associated missense mutation, MeCP2 T158A. We found that mice with T158A mutation show similar RTT-like phenotypes to that of Mecp2-null mice. T158A mutation decreases the binding of MeCP2 to methylated DNA and reduces MeCP2 protein stability. Mice with MeCP2 dysfunction also show age-dependent impairment of neuronal event-related potentials (ERPs) indicative of disrupted neural circuitry. Moreover, our ongoing work supports a role of MeCP2 in modulation of gene transcription and dendritic development in a cell-type specific manner. Together, these findings lead to a new series of questions pertaining to the pathogenic mechanisms of RTT. We propose to address them in the following specific aims: 1) To define the role of methyl-DNA binding of MeCP2 in the etiology of RTT-like phenotypes; 2) To dissect the role of MeCP2 in different neuronal cells regulating information processing; and 3) To investigate the molecular mechanisms by which MeCP2 modulates cell type-specific neuronal function. With the combined genetic, genomic, behavioral and neurophysiological approaches, we hope to not only reveal novel insight into the pathogenic mechanisms underlying RTT, but also to expedite the development of mechanism-based therapeutics that are focused on MeCP2 methyl-DNA binding and specific neuronal types. Moreover, our proposed study will provide the research community at large with innovative tools and resources to investigate the epigenetic mechanisms underlying a variety of biological processes and diseases.

描述（由申请人提供）：甲基-CPG结合蛋白2（MECP2）基因中的突变导致自闭症谱系障碍RETT综合征（RTT）。为了了解RTT的发病机理，我们先前开发并表征了小鼠模型，该模型概括了与RTT相关的错义突变MECP2 T158A。我们发现，具有T158A突变的小鼠显示出与MECP2-NULL小鼠相似的RTT样表型。 T158A突变降低了MECP2与甲基化DNA的结合，并降低了MECP2蛋白稳定性。具有MECP2功能障碍的小鼠还显示了与神经元事件相关电位（ERP）的年龄依赖性损害，指示神经回路破坏。此外，我们正在进行的工作支持MECP2在细胞类型的特定方式中的基因转录和树突状发育调节中的作用。总之，这些发现导致了与RTT的致病机理有关的一系列新问题。我们建议在以下特定目的中解决它们：1）定义MECP2在RTT样表型病因中的甲基-DNA结合的作用； 2）剖析MECP2在调节信息处理的不同神经元细胞中的作用； 3）研究MECP2调节细胞类型特异性神经元功能的分子机制。通过遗传，基因组，行为和神经生理学方法的组合，我们希望不仅揭示RTT潜在的致病机制的新颖见解，而且还可以加快基于机制的疗法的发展，这些疗法集中在MECP2甲基-DNA上类型。此外，我们提出的研究将为整个研究社区提供创新的工具和资源，以研究各种生物过程和疾病的表观遗传机制。