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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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氏病（AD）是一种毁灭性的神经退行性疾病，影响了约600万成人在美国，没有治愈或治疗方法有效地降低了疾病的进展。全基因组关联研究（GWAS）阐明了与AD相关的75个局部研究，但是因果变异疾病缔约的潜在基因或途径仍有待确定它们起作用调节高阶表型。基因组学与转录组学的整合可以告知常见遗传变异对分子表型的影响对细胞功能的影响。我的实验室有表明AD敏感性局部富含改变RNA水平和/或剪接的遗传变异体，以及这些变体通常位于富含髓样细胞的顺式调节元件中。但是，因果变体或基因对于与AD相关的大多数基因座，保持难以捉摸。该建议将为研究提供宝贵的资源试图描述GWAS风险基因座的因果变异，并将其连接到改变的细胞功能。奖励的巨大功能多样性对RNA分子的复杂前后，以及最丰富的转录后修饰是腺苷对肌苷（A-TO-I）RNA编辑。在蛋白质编码区域，这些基本特异性变化“重新解码”氨基酸序列，在非编码中区域，通过影响RNA的剪接，稳定性和亚细胞定位来编辑微型基因基因转录本，以及它们结合微RNA（miRNA）的能力。 RNA编辑活性中断了广泛报道了AD患者，但这是该疾病的结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。与AD相关的遗传变异调节A到I编辑。我将使用定量性状区域（QTL）映射到相关在脑和髓样细胞中，A-TO-I事件全基因组的RNA编辑水平的常见遗传变异。然后，我将采用先进的统计方法来确定A到I编辑的遗传调节剂是否居住在GWAS风险基因座的AD中。重要的是，我将实施适当的方法探测调解，以除了多效性或普通效应外，分析真正的因果基因调节途径协会。通过优先考虑受严格遗传调节的A到I编辑站点并解决它们有助于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的疗法的能力开发治疗方法广告。