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：
10656152
负责人：
Zhaolan Zhou
金额：
$ 52.03万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10656152
关键词：
Address Alleles Basic Science Behavioral Binding Biological Process Biotin Brain Cells Chromatin Classification Clinical Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Communities DNA Methylation Defect Development Diagnosis Disease Epigenetic Process Etiology Event-Related Potentials Female Functional disorder Funding Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Genome Genomic Segment Genomics Heterogeneity Heterozygote Impairment Intellectual functioning disability Interneurons Link Mediating Methyl-CpG-Binding Protein 2 Missense Mutation Modeling Molecular Mosaicism Mus Mutant Strains Mice Mutation Neurodevelopmental Disorder Neurons Nuclear Nucleic Acid Regulatory Sequences Pathogenesis Pathogenicity Pathway interactions Patients Pattern Phenotype Play Polymerase Prosencephalon RNA Polymerase II Reaction Research Resources Rett Syndrome Role Series Severities Specific qualifier value System Testing Therapeutic Time Transcription Elongation Transcription Initiation Transcriptional Regulation Translations X Inactivation behavioral phenotyping cell type conditional knockout differential expression epigenomics excitatory neuron exhibitions genetic approach girls histone modification improved in vivo information processing inhibitory neuron innovation insight interest male markov model mosaic mouse model mutant nervous system disorder neural circuit novel novel therapeutics programs protein expression synaptic function therapeutic development therapeutic target therapeutically effective tool transcriptome

项目摘要

Mutations in methyl-CpG binding protein 2 (MECP2) gene cause Rett Syndrome (RTT), a neurodevelopmental disorder that afflicts about 1 in 10,000 girls. To understand the pathogenesis of RTT, we previously developed and characterized mouse models recapitulating RTT-associated missense mutations, MeCP2 T158M and R106W, and examined MeCP2-dependent gene expression programs in neuronal cell types of interest. We found that 1) both mutations impair MeCP2 binding to chromatin, resulting in RTT-like phenotypes in mice, but, elevation of MeCP2 mutant protein expression increase the binding of MeCP2 to chromatin and ameliorate RTT-like phenotypes in vivo, raising a new direction to develop therapeutics for RTT; 2) MeCP2 plays a necessary and sufficient role in forebrain GABAergic interneurons mediating neuronal event-related potentials (ERPs), supporting a key role for MeCP2 to regulate information processing; and 3) By developing a Cre-dependent biotin tagging system, we uncovered that MeCP2 modulates gene transcription in a mutation-dependent, cell type-specific, and in both cell and non-cell autonomous manner, particularly in mosaic females. These findings have set the premise to uncover the molecular mechanisms by which MeCP2 modulates cell type-specific gene expression, investigate the molecular etiology of RTT in heterozygous females, and test the causality of MeCP2-dependent molecular pathways that underlie the pathogenesis of RTT. With the combined genetic, genomic, molecular and cellular approaches, we hope to not only reveal novel insight into the pathogenic mechanisms of RTT, but also to expedite the development of mechanism-based therapeutics to improve treatment for RTT. 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.

甲基 CpG 结合蛋白 2 (MECP2) 基因突变会导致 Rett 综合征 (RTT)，这是一种大约万分之一的女孩患有神经发育障碍。为了了解 RTT 的发病机制，我们之前开发并表征了重现 RTT 相关错义的小鼠模型 MeCP2 T158M 和 R106W 突变，并检查了 MeCP2 依赖性基因表达程序感兴趣的神经元细胞类型。我们发现 1) 两种突变都会损害 MeCP2 与染色质的结合，在小鼠中产生类似 RTT 的表型，但是 MeCP2 突变蛋白表达的升高会增加 MeCP2 与染色质结合并改善体内 RTT 样表型，为开发 RTT 疗法； 2）MeCP2在前脑GABA能中发挥必要且充分的作用中间神经元介导神经元事件相关电位 (ERP)，支持 MeCP2 的关键作用规范信息处理； 3) 通过开发 Cre 依赖性生物素标记系统，我们发现 MeCP2 以突变依赖性、细胞类型特异性和在细胞和非细胞自主方式，特别是在嵌合雌性中。这些发现确定了揭示 MeCP2 调节细胞类型特异性基因的分子机制的前提表达，研究杂合子女性 RTT 的分子病因学，并测试其因果关系 MeCP2 依赖性分子途径是 RTT 发病机制的基础。随着结合遗传、基因组、分子和细胞方法，我们希望不仅揭示对 RTT 的致病机制，同时也加快基于机制的治疗方法的开发改善 RTT 的治疗。此外，我们提出的研究将为研究界提供拥有大量创新工具和资源来研究各种潜在的表观遗传机制生物过程和疾病。