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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.

项目总结