Integrative genomic analysis of adenosine-to-inosine editing in Alzheimer's disease

阿尔茨海默病中腺苷至肌苷编辑的综合基因组分析

• 批准号: 10572263
• 负责人: Michael S Breen
• 金额: $ 16.62万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10572263
• 关键词: Address; Adenosine; Affect; Affinity; Alternative Splicing; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Apoptosis; Applied Genetics; Automobile Driving; Binding; Biological; Biological Process; Brain; Brain region; Cells; Central Nervous System; Clinical; Code; Cognitive; Complex; Computing Methodologies; Cytoplasm; Data; Dementia; Disease; Double-Stranded RNA; Elderly; Enzymes; Etiology; Functional disorder; Gene Expression; Genes; Genetic; Genetic Diseases; Genomics; Genotype; Guanosine; Human; Individual; Inosine; Interferons; Knowledge; Link; Maps; Masks; Methods; MicroRNAs; Modification; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuroglia; Neurons; Nuclear; Onset of illness; Outcome; Pathogenicity; Pattern; Population; Process; Quantitative Trait Loci; RNA; RNA Editing; RNA Sequences; RNA Splicing; RNA Stability; RNA-Binding Proteins; Regulation; Research; Resources; Role; Sampling; Severities; Severity of illness; Site; Structure; Tissues; Transcript; Transcriptional Regulation; Translation Initiation; Translational Regulation; Translational Repression; Translations; Work; base; brain cell; causal variant; cell type; cohort; data resource; design; disorder risk; dsRNA adenosine deaminase; genetic information; genome wide association study; genome-wide; genomic data; lens; neurobiological mechanism; neuropathology; new therapeutic target; normal aging; posttranscriptional; protein aminoacid sequence; risk variant; stress granule; success; therapeutic genome editing; therapeutic target; therapeutically effective; tool; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Post-transcriptional modifications by adenosine-to-inosine (A-to-I) RNA editing are a major contributor to the global diversity of RNA sequences in the human brain. A-to-I editing occurs either at an isolated adenosine (‘selective editing’) or across many neighboring adenosines in an extended region on the same transcript (‘hyper- editing’). These base-specific alterations occur across most neuronal and non-neuronal expressed genes, and are required for normal brain function. A-to-I editing has been shown to influence alternative splicing, recode amino acid sequences of proteins, alter the ability of miRNAs to bind to their target sites, and change the stability of RNA secondary structures. Moreover, recent work show that these modifications are tightly regulated in the brain, and changes in editing levels are tied to etiology of neurodevelopmental and neurodegenerative disorders, including Alzheimer’s disease (AD). Nevertheless, major gaps exist in understanding the neuropathological roles of A-to-I editing in the AD brain. The vast majority of sites are likely to be dynamically regulated among different cell types, brain regions in AD and across dementia severity. Yet, the status quo as it pertains to such context- dependent regulation of RNA editing can be summarized as little or none. Moreover, while most efforts have studied individual selective A-to-I editing sites independently, there is a complete dearth of research on the role of A-to-I hyper-editing and hyper-edited genes in AD, which have profound effects on transcriptional and translational regulation. Finally, while existing studies on the regulation of RNA editing mainly focused on the adenosine deaminase acting on RNA enzymes, the role of cis-acting genetic regulation (editing quantitative trait loci [edQTLs]) has been understudied and underpowered. This proposal will capitalize on the success of large- scale genomics and consortia efforts to elucidate functional and highly regulated RNA editing sites in normal aging and AD at a previously impossible scale. The current proposal is designed to overcome current knowledge gaps by: Aim 1) Addressing the unmet need for basic neuroscientific research that can capture fundamental regulation of RNA editing across multiple brain regions and cell types in normal aging and AD; Aim 2) Integrating individual genetic information from large cohorts to build powerful edQTL maps and uncover credible sets of AD risk loci that exert their pathogenic effects by changing RNA editing levels in the brain; Aim 3) Applying data- driven computational methods to annotate and prioritize functionally important RNA editing sites and hyper- edited genes strongly linked to AD, thereby advancing our understanding of the complex etiology of AD through the lens of RNA modifications. Results from this proposal will generate a more complete picture of the molecular and genetic landscape of AD, and will advance the identification of new therapeutic targets.

项目概要 腺苷到肌苷 (A-to-I) RNA 编辑的转录后修饰是导致 人脑中 RNA 序列的整体多样性发生在孤立的腺苷上。 （“选择性编辑”）或同一转录本上扩展区域中的许多相邻腺苷（“超 这些碱基特异性改变发生在大多数神经元和非神经元表达的基因中，并且 正常大脑功能所必需的 A 到 I 编辑已被证明会影响选择性剪接、重新编码。 蛋白质的氨基酸序列，改变 miRNA 与其靶位点结合的能力，并改变稳定性 此外，最近的研究表明这些修饰在RNA二级结构中受到严格调控。 大脑，编辑水平的变化与神经发育和神经退行性疾病的病因有关， 然而，对于神经病理学作用的理解仍存在重大差距。 AD 大脑中的 A 到 I 编辑的绝大多数位点可能在不同的区域之间受到动态调节。 AD 中的细胞类型、大脑区域以及痴呆症的严重程度。 此外，尽管大多数努力都具有RNA编辑的依赖性调节，但可以概括为很少或没有。 独立研究了个体选择性A-I编辑位点，对其作用有完整的深度研究 AD 中 A-to-I 超编辑和超编辑基因的研究，对转录和转录产生深远影响 最后，现有的RNA编辑调控研究主要集中在翻译调控上。 腺苷脱氨酶作用于RNA酶，顺式作用遗传调控的作用（编辑数量性状） 位点 [edQTLs]）尚未得到充分研究且动力不足。该提案将利用大规模的成功。 扩大基因组学和联盟的努力，以阐明正常情况下功能性和高度调控的 RNA 编辑位点 当前的提案旨在克服现有的知识。 目标 1) 解决基础神经科学研究的未满足需求，以捕获基本神经科学研究 正常衰老和 AD 中跨多个大脑区域和细胞类型的 RNA 编辑调节；目标 2) 整合； 来自大型群体的个体遗传信息，以构建强大的 edQTL 图谱并揭示令人信服的 AD 组 通过改变大脑中的 RNA 编辑水平发挥致病作用的风险位点；目标 3) 应用数据- 驱动计算方法来注释和优先考虑功能重要的 RNA 编辑位点和超 编辑与 AD 密切相关的基因，从而增进我们对 AD 复杂病因学的理解 该提案的结果将生成更完整的分子图景。 和 AD 的遗传景观，并将促进新治疗靶点的确定。