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：
10678925
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/10678925
关键词：
3-Dimensional 5&apos Untranslated Regions Adherent Culture Animal Model Area Behavioral Binding Biological Models Brain CGG repeat Cells Clinical Trials Data Development Disease Dissection Drosophila genus Drug Modulation Electrophysiology (science)FMR1 Fragile X Syndrome Functional disorder GABA Receptor Gene Expression Regulation Genetic Genomics Goals Human Human Development Hypermethylation In Vitro Induced pluripotent stem cell derived neurons Inherited Intellectual functioning disability Knowledge Learning Link Mediating Messenger RNA Metabotropic Glutamate Receptors Modeling Molecular Mus 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 neural new therapeutic target novel novel therapeutic intervention novel therapeutics preclinical study promoter screening single-cell RNA sequencing small molecule stem cell model stem cells synaptogenesis synergism technology development therapeutic development three-dimensional modeling tool transcriptome transcriptomics translatome

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.

项目概要脆性 X 综合征 (FXS) 是一种 X 连锁智力障碍 (ID) 疾病，最常见的原因是 FMR1 基因 5'-非翻译区的 CGG 重复序列扩展超过 200 个重复序列。导致 FMR1 启动子过度甲基化，从而导致 FMR1 表达丧失。近三年来，由于功能性脆性 X 智力迟钝蛋白 (FMRP) 的丧失而引起。自发现 FMR1 基因以来经过数十年的研究，人们对 FMRP 的功能有了很多了解其缺失的后果是，主要使用小鼠和果蝇模型系统。与信使核糖核蛋白 mRNP 和/或停滞多聚核糖体相关的 RNA 结合蛋白 FMRP 似乎参与突触局部蛋白质合成的调节。选择性 mRNA 翻译失调在表征潜在疾病方面取得了实质性进展。动物模型中的机制已导致调节代谢性药物的高度临床前研究取得成功然而，后续的人体临床试验基本上不成功，强调使用 FXS 小鼠模型开发人类 iPSC 衍生单层的不精确性。培养（2D）和三维（3D）类器官培养系统，概括了人类的主要特征大脑发育，提供了一个平台来模拟人类发育和疾病，以及更好地对于 FMRP 介导的人脑发育调节或治疗药物的筛选知之甚少。其可塑性的程度，这对于充分理解 FXS 的病理生理学至关重要。该中心的目的是采取系统的方法来研究FMRP如何调节人脑发育和电路功能，并使用我们建立的人体 2D 开发新的治疗方法来治疗 FXS。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系统鉴定FMRP在人脑发育和回路中的功能mRNA靶点我们还将使用这些 iPSC 模型作为转化工具来开发新的治疗方法。 FXS 中心汇集了一支拥有转录组学专业知识的优秀研究团队。分析、全基因组翻译分析（翻译组）、FMRP-RNA 相互作用组、单细胞基因组学、细胞类型特异性操作、活性和电路依赖性机制的剖析以及高通量小分子我们的协调努力将产生科学协同作用并显着推进我们的研究。了解 FMRP 介导的人脑发育和回路功能中的基因调控，并能够脆性 X 综合征的新疗法开发。