Defining the messenger RNP code in the brain

定义大脑中的信使 RNP 代码

基本信息

批准号：
8295914
负责人：
Eugene Wei-Ming Yeo
金额：
$ 59.89万
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：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8295914
关键词：
Affect Alternative Splicing Amyotrophic Lateral Sclerosis Angelman Syndrome Antibodies Antisense Oligonucleotides Behavioral Beryllium Binding Binding Sites Biochemical Bioinformatics Biological Assay Brain Cells Code Complex Defect Development Disease Double-Stranded RNA ES Cell Line Elements Epitopes Event Expression Library Fragile X Syndrome Functional RNA Future Genomics Germ Layers Goals Homeostasis Human Human Resources Immunoprecipitation Indium Lead Length Life Machine Learning Maps Mediating Mental disorders Messenger RNA Modeling Molecular Mus Muscular Dystrophies Neurodegenerative Disorders Neurologic Neurons Open Reading Frames Phenotype Pluripotent Stem Cells Problem Solving Process Proteins RNA RNA Binding RNA Interference RNA Processing RNA Splicing RNA Stability RNA, Messenger, Splicing RNA-Binding Proteins Regulation Regulatory Element Resources Ribosomes Role Schizophrenia Spinal Spinal Muscular Atrophy Structure Technology Translations autism spectrum disorder base crosslink genome wide association study genome-wide human RBM5 protein human embryonic stem cell human embryonic stem cell line in vivo insight lentiviral-mediated messenger ribonucleoprotein nerve stem cell nervous system disorder neuroregulation novel predictive modeling protein complex relating to nervous system

项目摘要

DESCRIPTION (provided by applicant): RNA binding proteins (RBPs) interact with functional RNA elements embedded within pre- and mature messenger RNA to form messenger ribonucleoprotein (mRNP) complexes. These interactions result in the faithful execution of RNA processing events such as pre-mRNA alternative splicing, RNA stability and translational control. Aberrant alterations in the interactions between the RBPs and their RNA elements ultimately lead to behavioral abnormalities and neurological developmental defects, which can often manifest as fatal diseases such as Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis or life-long debilitating behavioral abnormalities such as Prader-Willi/Angelman Syndromes, Schizophrenia and Autism Spectrum Disorder. These findings underscore the importance of investigating the roles of these RBPs in the brain. In particular, our project is aimed at systematically, using genome-wide biochemical and bioinformatic assays, identifying the functional RNA elements that are recognized by RBPs in mouse brain and human neurons. We will develop a novel resource of human pluripotent stem cells stably expressing tagged RBPs that can be differentiated into human neurons. This will enable the identification of RNA binding sites of 50 RBPs in human neural RNAs in a uniform and systematic manner using cutting-edge genomic approaches such as cross-linking and immunoprecipitation followed by high-throughput sequencing (CLIP- seq). To reveal the splicing, stability, and translational changes that are dependent on direct binding of these RBPs we will perform high-throughput sequencing of mRNAs (RNA-seq) and ribosome-protected fragments (RPFs). Finally, we will leverage our computational expertise to build predictive models using this genome-wide, multi-scale, mRNP code in the brain. PUBLIC HEALTH RELEVANCE: Over the last decade, defects in RNA binding proteins (RBPs) themselves or the interactions between RNA binding sites of RBPs have become recognized as increasingly responsible for neurological disease and mental disorders. This proposal seeks to establish the interactions among selected RBPs and their functional RNA elements in mammalian neurons. This will be a crucial first step in elucidating the RNA networks regulated by these RBPs in the brain.

描述（由申请人提供）：RNA结合蛋白（RBP）与嵌入前和成熟的Messenger RNA中的功能性RNA元件相互作用，形成信使核糖核蛋白（MRNP）复合物。这些相互作用导致忠实地执行RNA处理事件，例如MRNA替代剪接，RNA稳定性和转化控制。 Aberrant alterations in the interactions between the RBPs and their RNA elements ultimately lead to behavioral abnormalities and neurological developmental defects, which can often manifest as fatal diseases such as Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis or life-long debilitating behavioral abnormalities such as Prader-Willi/Angelman Syndromes, Schizophrenia and Autism Spectrum Disorder.这些发现强调了研究这些RBP在大脑中的作用的重要性。特别是，我们的项目采用全基因组生化和生物信息学测定法进行系统地，识别RBP在小鼠脑和人类神经元中识别的功能性RNA元素。我们将开发一种稳定地表达标记的RBP的人类多能干细胞的新型资源，可以分化为人类神经元。这将使人类神经RNA中的RNA结合位点以统一和系统的方式使用尖端的基因组方法（例如交叉链接和免疫沉淀），然后进行高通量测序（夹克）。为了揭示取决于这些RBP的直接结合的剪接，稳定性和翻译变化，我们将执行mRNA（RNA-SEQ）和核糖体保护片段（RPFS）的高通量测序。最后，我们将利用我们的计算专业知识来使用大脑中的全基因组，多尺度，MRNP代码来构建预测模型。公共卫生相关性：在过去的十年中，RNA结合蛋白（RBP）本身的缺陷或RNA结合位点之间的相互作用已被公认为是对神经系统疾病和精神疾病的日益造成的。该建议旨在在哺乳动物神经元中确定选定的RBP及其功能RNA元件之间的相互作用。这将是阐明这些RBP在大脑中调节的RNA网络的关键第一步。