Astroglia-Mediated Pathogenic Mechanisms in Fragile X Syndrome (FXS)

星形胶质细胞介导的脆性 X 综合征 (FXS) 致病机制

• 批准号: 10671282
• 负责人: Yongjie Yang
• 金额: $ 47.73万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671282
• 关键词: 3' Untranslated Regions; Acceleration; Affect; Astrocytes; Attenuated; Behavioral; Binding; Binding Sites; Biochemical; Brain; Cells; Data; Development; Disease; Down-Regulation; Electrophysiology (science); FMR1; Fragile X Syndrome; Funding; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Transcription; Human; Hyperactivity; Hypersensitivity; Image; Impaired cognition; In Vitro; Inherited; Injections; Intellectual functioning disability; Length; Mediating; Mediator; Messenger RNA; MicroRNAs; Microglia; Molecular; Morphology; Mus; Neurons; Nucleotides; Oligodendroglia; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Play; Proteome; RNA-Binding Proteins; Regulation; Role; Seizures; Sensory; Signal Transduction; Specific qualifier value; Synapses; Translational Regulation; Translations; Untranslated RNA; Up-Regulation; Virus; autistic; behavioral phenotyping; conditional knockout; in vivo; mRNA Transcript Degradation; mRNA Translation; memory acquisition; messenger ribonucleoprotein; mouse genetics; nerve stem cell; neurotransmission; postnatal; postnatal development; repetitive behavior; response; social; software development; synaptic function; synaptogenesis; transcriptome

Abstract Fragile X syndrome (FXS) is one of the most common inherited intellectual disabilities (ID) that is caused by transcriptional silencing of the Fmr1 gene and loss of its encoded fragile X messenger ribonucleoprotein (FMRP). FXS manifests with cognitive impairment, hyperactivity/seizure, sensory hypersensitivity, and several autistic features such as repetitive behaviors and social withdraw. FMRP has been shown to be primarily a RNA- binding protein that regulates translation of many mRNAs. In the mammalian CNS, astroglial cells play active and diverse roles in modulating synaptogenesis and synaptic functions, especially during postnatal development. How the loss of FMRP affects astroglial development and functions, especially underlying molecular mechanisms, just begin to be understood. MicroRNAs (miRs) are a class of noncoding RNAs with a mature length of 20-25 nucleotides that primarily bind to the 3’UTR of target mRNAs to significantly modulate gene expression by either inhibiting mRNA translation or inducing mRNA degradation. Biochemical and genetic evidence in neurons have implicated important roles of miR pathways in FMRP-mediated translational regulation. Additionally, miRs play key roles in the specification of neural progenitor cells and oligodendrocyte and microglia developmental maturation. Surprisingly, how miRs are involved in astroglial development especially postnatal molecular and morphological maturation is essentially unknown. This represents a significant obstacle to better understand astroglia-mediated pathogenic pathways in FXS. Based on our preliminary results and progress we made during previous funding period in understanding the role of astroglia in FXS pathogenesis, in this renewal, we propose the following aims: Aim 1: Determine the roles of miR-128-3p in regulating postnatal astroglial development; Aim 2: Determine the pathogenic roles of increased astroglial miR-128-3p in FXS. We have generated astroglial miR-128 conditional knock-out (Astro- miR-128 CKO) and astroglial miR-128/Fmr1 double conditional knock-out (Astro-miR-128/Fmr1 DCKO) mice and have generated a large amount of preliminary data to support our rationales and to demonstrate feasibility for proposed aims. We will employ mouse genetics, primary astroglial cultures, electrophysiology, virus injections, confocal and immunoEM imaging, and behavioral approaches to complete these aims. Outcomes from this project will begin to define specific miRs that regulate postnatal astroglial molecular and morphological maturation. In addition, the analysis of FXS-relevant synaptic and behavioral phenotypes on Astro-miR-128/Fmr1 DCKO mice will potentially provide a new astroglial target to modulate FXS disease development, thus will significantly advance our understanding about astroglial mechanisms in FXS pathogenesis.

抽象的 脆弱的X综合征（FXS）是造成的最常见的继承智障（ID）之一 通过对FMR1基因的转录沉默和其编码脆弱的X信使色素蛋白的丧失 （FMRP）。 FXS表现出认知障碍，多动症/癫痫发作，感觉超敏反应以及几种 自闭症特征，例如重复行为和社交戒断。 FMRP已被证明是主要的RNA- 结合蛋白，调节许多mRNA的翻译。在哺乳动物中枢神经系统中，星形胶质细胞发挥活性 在调节突触发生和突触功能中的作用，尤其是在产后发育过程中。 FMRP的损失如何影响星形胶质的发育和功能，尤其是基础分子 机制，就开始被理解。 microRNA（mirs）是一类非编码RNA，成熟 初级结合靶mRNA的3'UTR以显着调节基因的20-25个核动肽长度 通过抑制mRNA翻译或诱导的mRNA降解来表达。生化和遗传 神经元中的证据已在FMRP介导的翻译调节中实施了MIR途径的重要作用。 另外，miR在神经祖细胞的规范中起关键作用，少突胶质细胞和小胶质细胞 发展成熟。令人惊讶的是，mir如何参与星形胶质发展，尤其是产后 分子和形态成熟基本上未知。这代表了更好的障碍 了解Astroglia介导的FXS中的致病途径。 基于我们在以前的资助期间的初步结果和进步 星形胶质细胞在FXS发病机理中的作用，在这种续签中，我们提出以下目的：目标1：确定 miR-128-3p在调节产后星形胶质成长中的作用；目标2：确定致病作用 FXS中的星形胶质细胞miR-128-3p增加。我们已经产生了星形胶质细胞mir-128条件淘汰赛（Astro- miR-128 cko）和星形胶质细胞mir-128/fmr1双条件敲除（Astro-MIR-128/fmr1 DCKO）小鼠 并产生了大量的初步数据来支持我们的理由并证明可行性 对于拟议的目的。我们将采用小鼠遗传学，原发性星形型培养物，电生理学，病毒注射， 共焦和免疫成像以及完成这些目标的行为方法。结果 项目将开始定义调节产后星形胶质细胞和形态学的特定miRs 成熟。此外，在Astro-MIR-128/FMR1上的FXS相关突触和行为表型的分析 DCKO小鼠将有可能提供一个新的星形胶质细胞靶标，以调节FXS疾病的发展，因此将 显着提高了我们对FXS发病机理中星形胶质机制的理解。