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.

项目概要 阿尔茨海默病 (AD) 是一种毁灭性的神经退行性疾病，影响约 600 万成年人 在美国，尚无有效减缓疾病进展的治愈方法或治疗方法。 全基因组关联研究 (GWAS) 已阐明 75 个与 AD 相关的位点，但因果变异 疾病关联的潜在原因以及导致疾病发生的基因或途径仍有待确定。 它们的作用是调节高阶表型。基因组学与转录组学的整合可以为 常见遗传变异对细胞功能分子表型的影响。我的实验室有 表明 AD 易感位点富含改变 RNA 水平和/或剪接的遗传变异，并且 这些变异通常存在于骨髓细胞中富集的顺式调控元件中。然而，因果变异或基因 大多数与 AD 相关的位点仍然难以捉摸。该提案将为研究贡献宝贵的资源 寻求描述 GWAS 风险位点的因果变异，并将它们与改变的细胞功能联系起来。 复杂的转录前和转录后处理赋予 RNA 分子巨大的功能多样性，并且 最丰富的转录后修饰之一是腺苷到肌苷 (A-to-I) RNA 编辑。在 在蛋白质编码区，这些碱基特异性变化“重新编码”氨基酸序列，而在非编码区 A-to-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 转录本及其结合 micro-RNA (miRNA) 的能力。 RNA编辑活动被破坏 在 AD 患者中广泛报道，但这是否是疾病的结果或原因尚不清楚。这 该提案将通过检验以下假设来解决 RNA 编辑对 AD 病理生理学的贡献： AD 相关基因变异调节 A 到 I 编辑。我将使用数量性状位点 (QTL) 作图来关联 大脑和骨髓细胞基因组范围内 A 到 I 事件的 RNA 编辑水平的常见遗传变异。 然后，我将应用先进的统计方法来确定A-to-I编辑的遗传调节因子是否 存在于 AD 的 GWAS 风险位点。重要的是，我将实施适当的方法探索调解，以 除了遗传的多效性或虚假效应之外，解析真正的因果基因调控途径 协会。通过优先考虑受严格基因调控的 A 到 I 编辑位点并解决 他们帮助协调分子和细胞过程，这项工作的结果为 后续功能研究可以利用基于 RNA 的疗法的力量来开发治疗方法 广告。