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

• 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
• 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' 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

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'-非翻译区中 CGG 重复序列的扩展。 CGG 重复次数超过 200 次 导致 FMR1 启动子过度甲基化，导致 FMR1 表达丧失。 FXS 因而 由功能性脆性 X 智力低下蛋白 (FMRP) 缺失引起。在近三年的时间里 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 以及它缺失的后果，主要使用小鼠和果蝇模型系统。 FMRP 是一种选择性 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 似乎参与突触局部蛋白质合成的调节。 FMRP 的丢失导致 选择性 mRNA 的翻译失调。在表征基础疾病方面取得实质性进展 动物模型中的机制已经导致调节代谢性药物的临床前研究非常成功 谷氨酸和 GABA 受体。然而，后续的人体临床试验基本上不成功， 强调使用 FXS 鼠标模型的不精确性。人类 iPSC 衍生单层细胞的开发 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 筛选治疗药物。关于 FMRP 介导的人脑发育调节或 其可塑性程度，这对于充分理解 FXS 的病理生理学至关重要。总体目标 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，并开发新的治疗方法来治疗 FXS。使用我们已建立的人体 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 系统鉴定FMRP在人脑发育和回路中的功能mRNA靶点 功能。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 对于 FXS。该中心汇集了一支在转录组学方面拥有专业知识的优秀研究人员团队 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 分子筛选。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。