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)是一种毁灭性的神经退行性疾病，大约有600万成年人受到影响 在美国，没有治愈或有效减缓疾病进展的治疗方法。 全基因组关联研究已经阐明了75个与阿尔茨海默病相关的基因座，但因果变异 在疾病的基础上，关联仍有待确定，以及通过哪些基因或途径 它们起到调节高阶表型的作用。基因组学和转录组学的结合可以告诉我们 常见遗传变异对细胞功能相关分子表型的影响。我的实验室有 显示AD易感基因座富含改变RNA水平和/或剪接的遗传变异，以及 这些变异通常存在于富含髓系细胞的顺式调节元件中。然而，因果变异或基因 与AD相关的大多数基因座仍然难以捉摸。这项建议将为研究贡献宝贵的资源。 寻求描述GWA风险基因座的因果变异，并将它们与细胞功能改变联系起来。 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，以及 其中最丰富的转录后修饰是腺苷到肌苷(A到I)的RNA编辑。在……里面 蛋白质编码区，这些碱基特异的变化对氨基酸序列进行重新编码，并在非编码 区域，A-to-I通过影响RNA的剪接、稳定性和亚细胞定位来编辑微调基因 转录本及其结合微RNA(MiRNAs)的能力。中断的RNA编辑活动已被 在AD患者中被广泛报道，但这是否是该病的后果，还是原因尚不清楚。这 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相关的基因变异调节A-to-I编辑。我将使用数量性状座位(QTL)作图来关联 在全基因组的A-to-I事件中，大脑和髓系细胞中常见的RNA编辑水平的遗传变异。 然后，我将应用先进的统计方法来确定A-to-I编辑的遗传调节器 居住在阿尔茨海默病风险基因座。重要的是，我将实现适当的方法来探测调解，以 解析除遗传多效性或虚假效应之外的真正原因基因调控途径 联想。通过优先处理受严格基因调控的A-to-I编辑站点，并解决 他们帮助协调的分子和细胞过程，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 广告。