FMRP-mediated Regulation in Human Brain Development and Therapeutic Advancement

FMRP 介导的人脑发育和治疗进展调节

基本信息

批准号：
10271305
负责人：
PENG JIN
金额：
$ 160万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-25 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10271305
关键词：
3-Dimensional 5&apos Untranslated Regions Adherent Culture Animal Model Area Behavioral Biological Models Brain CGG repeat Cells Clinical Trials Data Development Disease Dissection Drosophila genus Electrophysiology (science)FMR1 Fragile X Syndrome Functional disorder GABA Receptor Gene Expression Regulation Genetic Genomics Goals Human Human Development Hypermethylation In Vitro Inherited Intellectual functioning disability Knowledge Link Mediating Messenger RNA Metabotropic Glutamate Receptors Modeling Molecular Mus Neurons Organoids Pharmaceutical Preparations Polyribosomes Protein Biosynthesis RNA RNA-Binding Proteins Regulation Research Research Personnel Rodent Role Signal Transduction Synapses System Technical Expertise Technology Testing Therapeutic Translational Regulation Translations Validation autism spectrum disorder cell type crosslinking and immunoprecipitation sequencing drug discovery follow-up functional loss genome editing genome-wide human disease human model in vivo induced pluripotent stem cell messenger ribonucleoprotein mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics preclinical study promoter relating to nervous system screening single-cell RNA sequencing small molecule stem cell model stem cells synaptogenesis synergism therapeutic development three dimensional cell culture three-dimensional modeling tool transcriptome transcriptomics translatome

3-Dimensional 5&apos Untranslated Regions Adherent Culture Animal Model Area Behavioral Biological Models Brain CGG repeat Cells Clinical Trials Data Development Disease Dissection Drosophila genus Electrophysiology (science)FMR1 Fragile X Syndrome Functional disorder GABA Receptor Gene Expression Regulation Genetic Genomics Goals Human Human Development Hypermethylation In Vitro Inherited Intellectual functioning disability Knowledge Link Mediating Messenger RNA Metabotropic Glutamate Receptors Modeling Molecular Mus Neurons Organoids Pharmaceutical Preparations Polyribosomes Protein Biosynthesis RNA RNA-Binding Proteins Regulation Research Research Personnel Rodent Role Signal Transduction Synapses System Technical Expertise Technology Testing Therapeutic Translational Regulation Translations Validation autism spectrum disorder cell type crosslinking and immunoprecipitation sequencing drug discovery follow-up functional loss genome editing genome-wide human disease human model in vivo induced pluripotent stem cell messenger ribonucleoprotein mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics preclinical study promoter relating to nervous system screening single-cell RNA sequencing small molecule stem cell model stem cells synaptogenesis synergism therapeutic development three dimensional cell culture three-dimensional modeling tool transcriptome transcriptomics translatome

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项目摘要

Project Summary Fragile X syndrome (FXS) is an X-linked disorder of intellectual disability (ID) that is most commonly due to the expansion of a CGG-repeat in the 5’-untranslated region of the FMR1 gene. CGG expansion beyond 200 repeats leads to hypermethylation of the FMR1 promoter, resulting in the loss of FMR1 expression. FXS is thereby caused by the loss of functional fragile X mental retardation protein (FMRP). Over the course of nearly three decades of research since the discovery of the FMR1 gene, much has been learned about the function of FMRP and the consequence of its absence, primarily using mouse and fruit fly model systems. FMRP is a selective RNA-binding protein associated with messenger ribonucleoprotein mRNPs and/or stalled polyribosomes that appears to be involved in the regulation of local protein synthesis at synapses. The loss of FMRP leads to dysregulated translation of selective mRNAs. Substantial progress in characterizing the underlying disease mechanisms in animal models has led to highly successful preclinical studies of drugs modulating metabotropic glutamate and GABA receptors. However, follow-up clinical trials in humans have been largely unsuccessful, highlighting the imprecision of using the mouse model of FXS. Development of human iPSCs-derived monolayer culture (2D) and three-dimensional (3D) organoid culture systems, which recapitulate key features of human brain development, have provided a platform to model human development and disease, as well as to better screen for therapeutic drugs. Little is known of FMRP-mediated regulation of human brain development or the extent of its plasticity, which is essential to fully understand the pathophysiology of FXS. The overarching goal of this Center is to take a systematic approach to investigate how FMRP may regulate human brain development and circuit functions, and develop novel therapeutic approaches to treat FXS. Using our established human 2D and 3D model systems as well as mouse models, we will determine the role of FMRP in human brain function and systematically identify the functional mRNA targets of FMRP in human brain development and circuit functions. We will also use these iPSC models as translational tools to develop novel therapeutic approaches for FXS. The Center brings together an outstanding team of investigators with expertise in transcriptomic analyses, genome-wide translation profiling (translatomes), FMRP-RNA interactomes, single cell genomics, cell type-specific manipulations, dissection of activity- and circuit-dependent mechanisms, and high-throughput small molecule screening. Our coordinated effort will create scientific synergy and significantly advance our understanding of FMRP-mediated gene regulation in human brain development and circuit functions and enable novel therapeutic development for fragile X syndrome.

项目摘要脆弱的X综合征（FXS）是一种X连锁的智障疾病（ID），最常见于 FMR1基因的5'-非翻译区域中CGG重复的扩展。 CGG扩展超过200重复导致FMR1启动子的高甲基化，导致FMR1表达的丧失。 FXS就是这样由功能性脆弱X智力低下蛋白（FMRP）的丧失引起。在近三个过程中自从发现FMR1基因以来，数十年的研究已经了解了FMRP的功能以及其缺席的结果，主要使用小鼠和果蝇模型系统。 FMRP是选择性 RNA结合蛋白与信使核糖核蛋白mRNP和/或停滞的多核糖体相关的RNA结合蛋白在突触下调节局部蛋白质合成的表现。 FMRP的损失导致选择性mRNA的翻译失调。表征潜在疾病的实质进展动物模型中的机制导致对调节代谢型的药物进行了非常成功的临床前研究谷氨酸和GABA受体。但是，人类的后续临床试验在很大程度上没有成功，突出显示了使用FXS的鼠标模型的实现。人类IPSC衍生的单层的开发培养（2D）和三维（3D）器官培养系统，这些系统概括了人类的关键特征大脑发育，为建模人类发展和疾病提供了一个平台，以及更好的筛选治疗药物。 FMRP介导的人脑发育的调节或其可塑性的程度，这对于完全了解FXS的病理生理至关重要。总体目标这个中心的是采用系统的方法来研究FMRP如何调节人脑发育和电路功能，并开发出新的治疗方法来治疗FXS。使用我们既定的人2d 和3D模型系统以及小鼠模型，我们将确定FMRP在人脑功能中的作用并系统地识别FMRP在人脑发育和电路中的功能mRNA靶标功能。我们还将使用这些IPSC模型作为翻译工具来开发新颖的治疗方法对于FXS。该中心汇集了一个杰出的调查员团队，具有转录组的专业知识分析，全基因组翻译分析（翻译），FMRP-RNA相互作用，单细胞基因组学，细胞特定类型的操作，活动和电路依赖机制的解剖以及高通量小分子筛选。我们协调的努力将创造科学协同作用，并显着提高我们的了解FMRP介导的基因调节在人脑发育和电路功能中的理解，并启用脆弱X综合征的新型热发育。