Systematic approaches to deciphering regulation and function of RNA editing in brain

破译大脑中 RNA 编辑调控和功能的系统方法

• 批准号: 10521265
• 负责人: Xinshu Grace Xiao
• 金额: $ 52.32万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10521265
• 关键词: 3' Untranslated Regions; ASD patient; Address; Adenosine; Affect; Alzheimer' s Disease; Amino Acid Sequence; Amyotrophic Lateral Sclerosis; Animals; Area; Autopsy; Bioinformatics; Biological Assay; Brain; Cells; Code; Cognition; Collection; Complement; Data; Data Set; Development; Disease; Double-Stranded RNA; Embryo; Enzymes; Evolution; Future; Gene Expression Regulation; Genes; Genetic Transcription; Genomics; Health; Human; Human Biology; Individual; Inosine; Introns; Life; Malignant Neoplasms; Mammals; Membrane; Mental Depression; Messenger RNA; Methodology; Methods; Modification; Molecular; Nervous System; Neurobiology; Neurodevelopmental Disorder; Neurologic Dysfunctions; Nucleotides; Organism; Pattern; Phenotype; Post-Transcriptional Regulation; Primates; Protein Family; Proteins; Publishing; RNA; RNA Editing; RNA Processing; RNA Sequences; RNA analysis; RNA-Binding Proteins; Regulation; Reporter; Reporting; Research; Role; Sampling; Schizophrenia; Series; Signal Transduction; Site; Technology; Testing; Tissues; Untranslated RNA; Untranslated Regions; Variant; Work; autism spectrum disorder; biological systems; cell type; comparison control; dsRNA adenosine deaminase; experimental study; genetic regulatory protein; high throughput screening; human disease; insight; neuropsychiatric disorder; neurotransmission; novel; success; transcriptome; transcriptome sequencing

Project Summary Recent advances in sequencing technologies and bioinformatic methodologies have enabled great progress in better understanding RNA processing, regulation and modification. RNA editing is a prevalent type of RNA modification where the RNA sequences are altered through insertion, deletion or substitution of nucleotides. In mammals, the most common type of RNA editing is adenosine to inosine (A-to-I) editing. A-to-I editing is essential for normal life and development. A handful of A-to-I editing sites have been discovered with critical roles in neuronal signaling, by modulating membrane excitability, neurotransmission plasticity and signal transduction. In addition, aberrant RNA editing has been implicated in human neuropsychiatric diseases, such as Autism, Alzheimer’s disease, depression, schizophrenia, and amyotrophic lateral sclerosis. While numerous RNA editing sites have been identified via RNA-sequencing (RNA-seq) and related technologies, major challenges exist in understanding the function and regulation of RNA editing. The vast majority of known human RNA editing sites reside in non- coding regions, such as introns and untranslated regions, that may confer regulatory function to the related gene, especially at the level of post-transcriptional regulation. Therefore, there is a great demand for in-depth studies of the functional impacts of RNA editing on post- transcriptional regulation. The regulatory mechanisms of RNA editing are poorly characterized. Except the ADAR enzymes, few proteins and their mechanisms of action have been examined for RNA editing. A major challenge is the lack of efficient and systematic methods to pinpoint novel regulators. In this project, we propose to extend our recent success at developing bioinformatic and experimental frameworks to address the above challenges. We will capitalize on the large collection of RNA-seq data sets derived from postmortem brain samples. We will develop and apply novel methodologies to make full use of these data sets, complemented by further bioinformatic prediction and high-throughput experimental testing, to predict and validate the molecular function of RNA editing and related regulatory mechanisms. This work will allow a previously unattained level of understanding of the molecular basis of RNA editing and provide new insights to the involvement of RNA editing in human biology.

项目概要 测序技术和生物信息方法学的最新进展使得 在更好地理解 RNA 加工、调控和修饰方面取得了巨大进展。核糖核酸 编辑是一种流行的 RNA 修饰类型，其中 RNA 序列通过以下方式改变： 核苷酸的插入、缺失或取代。在哺乳动物中，最常见的 RNA 类型 编辑是腺苷到肌苷（A-to-I）编辑。 A-to-I 编辑对于正常生活至关重要 发展。一些 A-to-I 编辑网站被发现在 神经信号传导，通过调节膜兴奋性、神经传递可塑性和信号 转导。此外，异常的 RNA 编辑与人类神经精神疾病有关。 疾病，如自闭症、阿尔茨海默病、抑郁症、精神分裂症和肌萎缩症 侧索硬化。虽然通过 RNA 测序已经鉴定出许多 RNA 编辑位点 （RNA-seq）和相关技术，主要挑战在于理解其功能和 RNA编辑的调控。绝大多数已知的人类 RNA 编辑位点位于非 编码区，例如内含子和非翻译区，可能赋予调节功能 相关基因，特别是在转录后调控水平。因此，有一个 对深入研究 RNA 编辑对术后功能影响的巨大需求 转录调控。 RNA 编辑的调控机制目前尚不清楚。 除 ADAR 酶外，很少有蛋白质及其作用机制被研究过 用于 RNA 编辑。一个主要挑战是缺乏有效和系统的方法来精确定位 新颖的监管机构。在这个项目中，我们建议延续我们最近在开发方面取得的成功 应对上述挑战的生物信息学和实验框架。我们将大写 来自死后大脑样本的大量 RNA-seq 数据集。我们将 开发和应用新的方法来充分利用这些数据集，并辅之以 进一步的生物信息预测和高通量实验测试，以预测和验证 RNA编辑的分子功能及相关调控机制。这项工作将允许 对 RNA 编辑的分子基础的理解达到了前所未有的水平，并提供了 RNA 编辑参与人类生物学的新见解。