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）基因的突变引起RETT综合征（RTT），A 神经发育障碍，大约有10,000名女孩中有1个。要了解RTT的发病机理，我们以前开发并表征了鼠标模型，概括了与RTT相关的错义突变，MECP2 T158M和R106W，并检查了MECP2依赖性基因表达程序神经元细胞类型的兴趣。我们发现1）两个突变都会损害MECP2与染色质结合，导致小鼠的RTT样表型，但是，MECP2突变蛋白表达的升高会增加 MECP2与体内的染色质和改善RTT样表型的结合，从而提高了一个新方向为RTT开发治疗剂； 2）MECP2在前脑gabaergic中起必要和足够的作用介导神经元事件相关电位（ERP）的中间神经元支持MECP2的关键作用调节信息处理； 3）通过开发依赖CRE的生物素标记系统，我们发现MECP2在突变依赖性，细胞类型特异性和中调节基因转录细胞和非细胞自主方式，尤其是在马赛克女性中。这些发现设定了揭示MECP2调节细胞类型特异性基因的分子机制的前提表达，研究RTT在杂合雌性中的分子病因，并检验 MECP2依赖性分子途径是RTT发病机理的基础。与总和遗传，基因组，分子和细胞方法，我们希望不仅能揭示对这种新的见解 RTT的致病机制，但也加快基于机制的治疗剂的发展改善RTT的治疗。此外，我们提出的研究将为研究社区提供具有创新工具和资源的大型，以调查各种各样的表观遗传机制生物过程和疾病。