Translational Control by the Fragile X Mental Retardation Protein

脆性 X 智力迟钝蛋白的翻译控制

基本信息

批准号：
9199419
负责人：
SIMPSON JOSEPH
金额：
$ 35.48万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9199419
关键词：
American Amino Acids Animal Model Behavioral Binding Binding Proteins Biochemical Biological Assay Brain Cessation of life Childhood Code Complex Cryoelectron Microscopy Data Development Disease Drosophila FMR1 protein Drosophila genus Drosophila inturned protein Drug Targeting Exhibits FMR1 FMRP FXR1 gene FXR2 gene Facioscapulohumeral Muscular Dystrophy Fluorescence Fragile X Syndrome G-Quartets Genes Genetic Genetic Transcription Goals Human Human Cell Line In Vitro Inherited Intellectual functioning disability Laboratories Mammals Mental Retardation Messenger RNA Molecular Monitor Mus Muscle Development Muscular Dystrophies Myocardium Patients Phenotype Prevalence Protein Biosynthesis Proteins RNA RNA-Binding Proteins Regulation Reporter Resolution Ribosomes Role Seizures Skeletal Muscle Specificity Structure System Techniques Transgenic Organisms Translations autistic behaviour base biophysical techniques experimental study fetal fly in vivo insight interest mRNA Expression male myogenesis nervous system disorder novel therapeutics paralogous gene protein complex protein function public health relevance tool translation factor

项目摘要

DESCRIPTION (provided by applicant) Fragile X syndrome is a disease that afflicts about 100,000 Americans and about 3 million people worldwide, resulting in intellectual disability, childhood seizures, and autistic behavior i the patients. The disease is caused by the transcriptional silencing of the fragile X mental retardation 1 gene (FMR1). FMR1 gene codes for a RNA-binding protein, the fragile X mental retardation protein (FMRP), which is highly expressed in the brain and is essential for the normal development of the brain. Mammals have two autosomal paralogs of FMRP designated as fragile X related 1 and 2 (FXR1 and FXR2) proteins. FXR1 is essential for myogenesis and the altered expression of FXR1 causes facioscapulohumeral muscular dystrophy, the most prevalent form of muscular dystrophy. Inactivation of FXR2 does not cause a disease in humans; however, loss of both FMRP and FXR2 results in a more severe form of FXS in mice and Drosophila. Thus, FMRP and FXR2 appear to have overlapping functions in the brain, whereas FXR1 is more critical for muscle development. FMRP, FXR1 and FXR2 have been implicated in regulating the translation of several mRNAs. However, the precise mechanism by which these proteins regulate the expression of these mRNAs is unknown. The goal of the proposed study is to understand the molecular mechanism underlying the regulation of protein synthesis by FMRP, FXR1 and FXR2. We have strong initial results showing that FMRP can bind directly to the 80S ribosome to regulate protein synthesis. In Specific Aim 1, we will dissect the mechanism of translational control by Drosophila FMRP. In Specific Aim 2, we will focus on the mechanism of translational control by human FMRP, FXR1 and FXR2. For both specific aims, we will use a robust in vitro translation system and quantitative biophysical methods that have been developed in our laboratory, and in vivo studies, using human cell lines and transgenic Drosophila. These functional analyses, in conjunction with the proposed high-resolution cryo-electron microscopy, will significantly advance our understanding of the molecular mechanism used by FMRP, FXR1 and FXR2 to regulate protein synthesis. Results of these studies will provide useful insights in identifying potential drug targets to treat fragile X syndrome and facioscapulohumeral muscular dystrophy.

描述（由申请人提供）脆性 X 综合征是一种困扰约 10 万美国人和全球约 300 万人的疾病，导致患者出现智力障碍、儿童癫痫发作和自闭症行为（FMR1 基因编码 RNA 结合蛋白，即脆性 X 智力）。延迟蛋白（FMRP），在大脑中高度表达，对于哺乳动物有 FMRP 的两种常染色体旁系同源物，称为脆性 X 相关 1 和 2（FXR1 和 FXR2）蛋白，FXR1 对于肌肉生成至关重要，FXR1 表达的改变会导致面肩肱型肌营养不良症，这是最常见的肌肉萎缩症。 FXR2 失活不会导致人类疾病；然而，FMRP 和 FXR2 的缺失会导致更多疾病。因此，FMRP 和 FXR2 在小鼠和果蝇中似乎具有重叠的功能，而 FXR1 对于肌肉发育更为重要。这些蛋白质调节这些 mRNA 表达的确切机制尚不清楚。本研究的目的是了解 FMRP 调节蛋白质合成的分子机制。 FXR1 和 FXR2 的初步结果表明 FMRP 可以直接结合 80S 核糖体来调节蛋白质合成。果蝇 FMRP 的翻译控制机制在特定目标 2 中，我们将重点关注人类 FMRP、FXR1 和 FXR2 的翻译控制机制。对于这两个特定目标，我们将使用强大的体外翻译系统和定量生物物理方法。我们的实验室和体内研究已经使用人类细胞系和转基因果蝇进行了开发，这些功能分析与所提出的高分辨率冷冻电子显微镜相结合，将显着改善。我们对 FMRP、FXR1 和 FXR2 用于调节蛋白质合成的分子机制的理解进展将为识别治疗脆性 X 的潜在药物靶点提供有用的见解。综合征和面肩肱型肌营养不良症。