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: 10443845
• 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/10443845
• 关键词: 3-Dimensional; 5' 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

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 脆性X综合征（FXS）是一种X连锁的智力残疾（ID）疾病，最常见的原因是 FMR 1基因5 ′-非翻译区CGG重复序列的扩增。CGG扩增超过200个重复 导致FMR 1启动子的超甲基化，导致FMR 1表达的丧失。因此，FXS 这是由于功能性脆性X智力低下蛋白（FMRP）的缺失造成的。在近三年的时间里， 自FMR 1基因发现以来，经过几十年的研究，人们对FMRP的功能有了更多的了解 以及其缺失的后果，主要使用小鼠和果蝇模型系统。FMRP是一种选择性的 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， 似乎参与调节突触处的局部蛋白质合成。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 动物模型中的机制导致了调节代谢性药物的非常成功的临床前研究 谷氨酸和GABA受体。然而，后续的人体临床试验基本上没有成功， 突出了使用FXS小鼠模型的不精确性。人iPSC衍生的单层的开发 培养（2D）和三维（3D）类器官培养系统，其概括了人类细胞的关键特征。 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 其可塑性的程度，这是必不可少的，以充分了解FXS的病理生理。总体目标 本中心的主要任务是系统地研究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。使用我们建立的人类2D模型 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 并系统地鉴定了FMRP在人脑发育和回路中的功能mRNA靶点， 功能协调发展的我们还将使用这些iPSC模型作为翻译工具来开发新的治疗方法 关于FXS该中心汇集了一支优秀的研究团队，他们在转录组学方面具有专业知识。 分析，全基因组翻译谱（translatomes），FMRP-RNA相互作用组，单细胞基因组学，细胞 类型特异性操作，活动和电路依赖性机制的解剖，以及高通量小分子生物学。 分子筛选我们的协调努力将创造科学的协同作用，并大大推进我们的 了解人类大脑发育和回路功能中FMRP介导的基因调节，并使 脆性X综合征的新治疗进展