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 通过腺苷对肌苷（A-TO-I）RNA编辑进行的转录后修饰是主要的贡献者 人脑中RNA序列的全球多样性。 A到I编辑发生在孤立的腺苷上 （“选择性编辑”）或在同一转录本上的扩展区域中的许多相邻腺苷（'Hyper- 编辑’）。这些基础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，以及 正常的大脑功能需要。 A-to-i编辑已显示会影响替代剪接，重新编码 蛋白质的氨基酸序列，改变miRNA与目标位点结合的能力，并改变稳定性 RNA二级结构。此外，最近的工作表明，这些修改在 大脑以及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 包括阿尔茨海默氏病（AD）。然而，理解神经病理学角色的主要差距 在广告大脑中的A到I编辑。绝大多数站点可能会在不同的不同 细胞类型，AD和整个痴呆症严重程度的大脑区域。但是，与此上下文有关的现状 - RNA编辑的依赖调节可以总结为很少或无。而且，虽然大多数努力 独立研究的个人选择性A-to-I编辑站点，有关该角色的完整研究已完全死亡 AD中的A到I超编辑和超编辑的基因，这些基因对转录和 翻译法规。最后，尽管现有关于RNA编辑调节的研究主要集中在 作用于RNA酶的腺苷脱氨酶，顺式作用遗传调节的作用（编辑定量性状 局部[edqtls]）已被理解和不足。该提议将利用大型的成功 规模基因组学和财团努力阐明正常功能和高度调节的RNA编辑位点 以前不可能的规模衰老和广告。当前的建议旨在克服当前的知识 差距：目标1）满足对基本神经科学研究的未满足的需求，该研究可以捕获基本 正常衰老和AD中多个大脑区域和细胞类型的RNA编辑调节；目标2）整合 来自大型同类人群的个人遗传信息，建造强大的EDQTL地图和发现可靠的广告集 风险基因座通过改变大脑中的RNA编辑水平来发挥致病作用；目标3）应用数据 - 驱动的计算方法来注释和优先考虑功能上重要的RNA编辑位点和超级 编辑的基因与AD密切相关，从而通过 RNA修饰的镜头。该提案的结果将产生分子的更完整图片 和AD的遗传格局，并将推进对新的治疗靶标的识别。