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

基本信息

批准号：
10308097
负责人：
Xinshu Grace Xiao
金额：
$ 55.23万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
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/10308097
关键词：
3&apos Untranslated Regions ASD patient Address Adenosine Affect Alzheimer&apos 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 structure 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 adenosine deaminase autism spectrum disorder biological systems cell type experimental study genetic regulatory protein high throughput screening human disease insertion/deletion mutation insight neuropsychiatric disorder neurotransmission novel success transcriptome transcriptome sequencing

项目摘要

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.

项目摘要测序技术和生物信息学方法的最新进展已启用更好地理解RNA处理，调节和修改方面的巨大进展。 RNA 编辑是一种普遍的RNA修饰类型，其中RNA序列通过插入，缺失或替代核苷酸。在哺乳动物中，最常见的RNA类型编辑是腺苷（A-TO-I）编辑的腺苷。 A到我的编辑对于正常生活至关重要发展。已经发现了少数A到I编辑网站在神经元信号传导，通过调节膜兴奋性，神经传递性可塑性和信号转导。此外，人类神经精神病学已暗示异常的RNA编辑疾病，例如自闭症，阿尔茨海默氏病，抑郁症，精神分裂症和肌萎缩症侧硬化。虽然已经通过RNA测序确定了许多RNA编辑位点（RNA-seq）和相关技术，在理解功能和 RNA编辑的调节。绝大多数已知的人类RNA编辑站点都存在于非 - 编码区域，例如介绍和未翻译区域，可能赋予调节功能相关基因，尤其是在转录后调节的水平上。因此，有一个对RNA编辑对后期的功能影响的深入研究的巨大需求转录调节。 RNA编辑的调节机制的特征很差。除了ADAR酶以外，几乎没有蛋白质及其作用机制已被检查用于RNA编辑。一个主要的挑战是缺乏高效和系统的方法来查明新颖的监管机构。在这个项目中，我们建议扩大我们最近在开发方面的成功生物信息学和实验框架以应对上述挑战。我们将资本化在大量的RNA-seq数据集中，这些数据集从尸体后脑样本中得出。我们将开发和应用新颖的方法以充分利用这些数据集，由进一步的生物信息学预测和高通量实验测试，以预测和验证 RNA编辑和相关调节机制的分子功能。这项工作将允许以前对RNA编辑的分子基础的未迹法的理解水平并提供 RNA编辑在人类生物学中的参与的新见解。