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Understanding the NMD regulatory path from genetic variation to phenotypes

了解 NMD 从遗传变异到表型的调控路径

基本信息

批准号：
10714885
负责人：
Liang Chen
金额：
$ 29.89万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714885
关键词：
Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Award Blood specimen Brain Brain Diseases Brain imaging Bypass Candidate Disease Gene Catalogs Clinical Research Clinical Trials Cohort Studies Computing Methodologies Copy Number Polymorphism Data Development Disease Disease Progression Etiology Explosion Future Gene Expression Genes Genetic Variation Genomics Genotype Genotype-Tissue Expression Project Homeostasis Human Individual Intellectual functioning disability Investigation Link Mediating Modeling Molecular Mutation Nerve Degeneration Neurons Nonsense Codon Outcome Parents Pathogenesis Patients Phenotype Physiological Play Population Probability Public Health Quantitative Trait Loci RNA Processing Regulation Reporting Research Resources Risk Assessment Risk Factors Role Sampling Statistical Methods Testing Therapeutic Tissues Transcript Translations Variant autism spectrum disorder brain tissue causal variant cohort feeding frontotemporal lobar dementia amyotrophic lateral sclerosis genetic variant genome wide association study genome-wide mRNA Decay mRNA Surveillance neural neurodevelopment neuron loss neuroprotection neurotoxicity novel personalized medicine pre-clinical predictive modeling tau Proteins tau mutation therapeutic development trait transcriptome

项目摘要

PROJECT SUMMARY Identifying new molecular mechanisms of Alzheimer's disease (AD) pathogenesis is urgent. Regulation of RNA processing and translation can play a vital role in AD. Nonsense-mediated mRNA decay (NMD) is a translation-dependent mRNA surveillance mechanism to degrade error-containing “faulty” transcripts as well as many naturally occurring “normal” transcripts. Multiple lines of evidence support the essential role of NMD in neural development, neural homeostasis, and neural degeneration. More recent studies show that deficits in the overall activity of NMD causally mediate tau-induced neurotoxicity, and the reactivation of NMD in defective neurons is neuroprotective. This supplement application built upon our parent award will systematically investigate the dysregulation of NMD as a risk factor and possible disease mechanism contributing to AD development. Our parent R01 project has revealed the genome-wide landscape of genetic variants associated with NMD regulation (i.e., NMD- QTLs) in the natural population of Genotype-Tissue Expression (GTEx). NMD-QTLs are much more likely to colocalize with disease SNPs, especially those associated with brain diseases. Brain tissues have distinct NMD-QTL signatures, particularly the disease-related NMD-QTLs. Notably, among the 1779 nonredundant AD-associated SNPs reported in the Genome-Wide Association Studies (GWAS) catalog, 111 are NMD-QTLs, further suggesting an essential role of NMD in AD. Guided by promising preliminary data, we hypothesize that systematical analyses of NMD regulation in the brain using public patient data and omics resources will be critical to dissecting novel mechanisms of AD pathology. In this supplement, we will integrate NMD dysregulation as a mechanism to explain AD-associated genetic variants and prioritize causal genes for AD. Successful completion of this project will be the prelude to understanding the role of NMD in AD.

项目总结