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.

项目摘要 通过腺苷到肌苷（A-to-I）RNA编辑的转录后修饰是导致细胞凋亡的主要原因。 人类大脑中RNA序列的全球多样性。A-to-I编辑发生在分离的腺苷 （“选择性编辑”）或在同一转录本上延伸区域中的许多相邻腺苷上（“超编辑”）， 编辑“）。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， 是正常大脑功能所必需的A-to-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miRNAs与其靶位点结合的能力，并改变其稳定性。 RNA二级结构此外，最近的研究表明，这些修饰在细胞中受到严格的调控。 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学有关， 包括阿尔茨海默病（AD）。然而，在理解神经病理学作用方面存在重大差距， AD大脑中的A对I编辑。绝大多数网站可能会受到不同的动态监管， 细胞类型，AD和痴呆严重程度的大脑区域。然而，与这种背景相关的现状- RNA编辑的依赖性调节可以概括为很少或没有。此外，虽然大多数努力 我独立研究了个别的选择性A到I编辑网站，完全缺乏对它的作用的研究。 AD中的A-to-I超编辑和超编辑基因，它们对转录和 翻译调节最后，虽然现有的关于RNA编辑调控的研究主要集中在 腺苷脱氨酶作用于RNA酶，顺式作用的遗传调控作用（编辑数量性状 [编辑]基因座[edQTL]）研究不足，效力不足。该提案将利用大型企业的成功- 规模基因组学和财团的努力，以阐明功能和高度调控的RNA编辑位点，在正常 老龄化和阿尔茨海默病在一个以前不可能的规模。目前的建议旨在克服目前的知识 目标1）解决基础神经科学研究的未满足需求， 在正常衰老和AD中跨多个脑区域和细胞类型的RNA编辑调节;目的2）整合 从大型群体中获得个体遗传信息，以构建强大的edQTL图谱并发现可信的AD集 通过改变大脑中的RNA编辑水平来发挥其致病作用的风险位点;目的3）应用数据- 驱动的计算方法来注释和优先排序功能重要的RNA编辑位点和超- 编辑与AD密切相关的基因，从而通过以下方式推进我们对AD复杂病因学的理解： RNA修饰的透镜。从这个建议的结果将产生一个更完整的图片的分子 和遗传景观的AD，并将推进新的治疗靶点的识别。