Examining the genetic regulation of A-to-I editing and mediation of Alzheimer's disease

检查 A 到 I 编辑的基因调控和阿尔茨海默氏病的介导

• 批准号: 10749631
• 负责人: Winston Hirschler Cuddleston
• 金额: $ 4.75万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749631
• 关键词: Adenosine; Adopted; Adult; Affect; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amino Acid Sequence; Applied Genetics; Autopsy; Award; Binding; Biological; Biological Markers; Blood; Brain; Brain region; Catalogs; Cell Lineage; Cell physiology; Cells; Central Nervous System; Chromosome Mapping; Code; Collection; Complex; DNA; Data; Disease; Disease Progression; Early Diagnosis; Etiology; Event; Foundations; Functional disorder; Future; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genome Mappings; Genomics; Genotype; Heritability; Histopathology; Homeostasis; Human; Impaired cognition; Inflammatory; Inosine; Interferons; Maps; Mediating; Mediation; Meta-Analysis; Methodology; Methods; MicroRNAs; Microglia; Modification; Molecular; Myelogenous; Myeloid Cells; Natural Immunity; Neurodegenerative Disorders; Neuroimmunomodulation; Open Reading Frames; Outcome; Pathway interactions; Patients; Peripheral; Phenotype; Population; Quality of life; Quantitative Trait Loci; RNA; RNA Editing; RNA Splicing; Regulation; Regulator Genes; Regulatory Element; Regulatory Pathway; Reporting; Resolution; Resources; Risk; Role; Senile Plaques; Signal Transduction; Site; Solid; Sorting; Specificity; Statistical Methods; Susceptibility Gene; Symptoms; Testing; Therapeutic; Tissues; Transcript; Transcription Process; United States; Untranslated RNA; Variant; Work; base; biomarker development; brain cell; brain tissue; causal variant; cell type; cohort; disorder risk; extracellular; follow-up; gene function; genetic approach; genetic architecture; genetic association; genetic variant; genome wide association study; genome-wide; genomic data; improved; molecular phenotype; monocyte; neuroinflammation; novel; pleiotropism; posttranscriptional; response; risk variant; targeted treatment; tau aggregation; therapeutic RNA; therapeutic development; therapeutic target; trait; transcriptome sequencing; transcriptomics; validation studies

Project Summary Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, affecting approximately 6 million adults in the United States, for which there is no cure or treatments which effectively slow progression of the disease. Genome-wide association studies (GWAS) have illuminated 75 loci associated with AD, but the causal variants underlying the disease-associations remain to be identified, along with the genes or pathways through which they act to regulate higher-order phenotypes. The integration of genomics with transcriptomics can inform the influence of common genetic variation on molecular phenotypes consequential to cellular function. My lab has shown that AD susceptibility loci are enriched for genetic variants which alter RNA levels and/or splicing, and these variants often lie in cis-regulatory elements enriched in myeloid cells. However, causal variants or genes remain elusive for most loci associated with AD. This proposal will contribute a valuable resource for research seeking to describe causal variants at GWAS risk loci and connect them to altered cellular function. Intricate pre- and post-transcriptional processing of awards vast functional diversity to RNA molecules, and among the most abundant post-transcriptional modifications is adenosine-to-inosine (A-to-I) RNA editing. In protein-coding regions, these base-specific changes “recode” amino acid sequences, and in non-coding regions, A-to-I editing fine-tunes genes by influencing the splicing, stability, and subcellular localization of RNA transcripts, along with their ability to bind micro-RNAs (miRNAs). Disrupted RNA editing activity has been widely reported in AD patients, but whether this is a consequence of the disease, or cause is not clear. This proposal will address the contributions of RNA editing to AD pathophysiology by testing the hypothesis that AD-associated genetic variants modulate A-to-I editing. I will use quantitative trait loci (QTL) mapping to relate common genetic variation to level of RNA editing at A-to-I events genome-wide in the brain and myeloid cells. Then, I will apply advanced statistical approaches to determine whether the genetic regulators of A-to-I editing reside in GWAS risk loci for AD. Importantly, I will implement appropriate methodology probing mediation, to parse bona fide causal gene regulatory pathways apart from pleiotropy or spurious effects of genetic associations. By prioritizing A-to-I editing sites which are subject to tight genetic regulation and resolving the molecular and cellular processes they help to orchestrate, the results from this work lay critical foundation for follow-up functional studies which can harness the power of RNA based therapeutics to develop treatments for AD.

项目摘要 阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，影响约600万成年人 在美国，没有治愈或有效减缓疾病进展的治疗方法。 全基因组关联研究（GWAS）已经阐明了75个与AD相关的基因座，但致病变异 潜在的疾病关联仍有待确定，沿着的基因或途径， 它们的作用是调节高级表型。基因组学与转录组学的整合可以为基因组学提供信息。 常见遗传变异对细胞功能分子表型的影响。我的实验室 显示AD易感性基因座富含改变RNA水平和/或剪接的遗传变体， 这些变异体通常存在于骨髓细胞中富集的顺式调节元件中。然而，因果变异或基因 对于大多数与AD相关的基因座仍然是难以捉摸的。这一建议将为研究提供宝贵的资源 试图描述GWAS风险位点的因果变异，并将其与改变的细胞功能联系起来。 复杂的转录前和转录后加工赋予RNA分子巨大的功能多样性， 在最丰富的转录后修饰中，有腺苷-肌苷（A-to-I）RNA编辑。在 在蛋白质编码区，这些碱基特异性的变化“重新编码”氨基酸序列，在非编码区， 区域，A到I编辑通过影响RNA的剪接、稳定性和亚细胞定位来微调基因 转录物，沿着它们结合微小RNA（miRNA）的能力。RNA编辑活动被破坏， 在AD患者中广泛报道，但这是否是疾病的后果或原因尚不清楚。这 该提案将通过测试以下假设来解决RNA编辑对AD病理生理学的贡献， AD相关的遗传变异调节A到I编辑。我将使用数量性状基因座（QTL）作图， 在脑和骨髓细胞中，常见的遗传变异与全基因组A-to-I事件的RNA编辑水平有关。 然后，我将应用先进的统计方法，以确定是否基因调控的A到I编辑 存在于AD的GWAS风险位点。重要的是，我将实现适当的方法来探测中介， 分析真正的因果基因调控途径，除了基因的多效性或假效应。 协会.通过优先考虑受到严格遗传调控的A-to-I编辑位点， 分子和细胞过程，他们帮助编排，从这项工作的结果奠定了关键的基础， 后续的功能研究，可以利用基于RNA的治疗方法的力量来开发治疗方法， AD.