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

• 批准号: 10594582
• 负责人: Liang Chen
• 金额: $ 32.06万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 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/10594582
• 关键词: Acceleration; Address; Binding Proteins; Binding Sites; Biochemical; Biochemistry; Biological; Biology; Cell Cycle; Computer Models; Computing Methodologies; Defect; Development; Disease; Dropout; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic Variation; Genomics; Genotype-Tissue Expression Project; Goals; Health; Heterogeneity; Homeostasis; Human; Immunity; In Vitro; Individual; Joints; Knowledge; Maps; Mediating; Messenger RNA; Methods; Mission; Modeling; Molecular; Molecular Biology; Mutation; Pathway interactions; Phenotype; Positioning Attribute; Post-Transcriptional Regulation; Prevention; Process; Production; Protein Truncation; Public Health; Quality Control; Quantitative Trait Loci; RNA; RNA Binding; RNA-Binding Proteins; Regulation; Research; Resources; Role; Specificity; Spermatogenesis; Statistical Methods; Statistical Models; Stereotyping; Therapeutic; Therapeutic Intervention; Transcript; United States National Institutes of Health; Variant; biological adaptation to stress; genetic variant; high throughput screening; improved; insight; mRNA Decay; mRNA Stability; mRNA Surveillance; neural; novel; posttranscriptional; power analysis; prevent; preventive intervention; transcriptome sequencing; transcriptomics

PROJECT SUMMARY There are fundamental gaps in our understanding of the regulatory mechanisms of nonsense- mediated mRNA decay (NMD). Originally conceived as a quality-control checkpoint to recognize and degrade aberrant transcripts, NMD has become appreciated as a post-transcriptional gene regulation mechanism to fine-tune expression of many non-aberrant endogenous mRNAs. However, despite a plethora of biochemical characterization on the NMD pathway, the mechanism of NMD regulation and the criteria for NMD target selection are poorly understood. Our long-term goal is to develop computational methods to discover the principles of gene expression regulation and explore how variations or defects in gene regulation cause phenotypic variation or disease. The overall objective of this application is to elucidate the context-dependent NMD regulation of individual genes through genetical genomics. Genetic variants associated with changes in gene expression (expression quantitative trait loci, eQTLs) are being catalogued in increasingly large-scale human studies, such as the Genotype-Tissue Expression (GTEx) project. We will take advantage of this unprecedented resource to dissect NMD control and to discover NMD regulatory rules in a systematic and unbiased manner. Traditional biochemical and molecular approaches are essential to deciphering NMD mechanism but are slow in progress with intrinsic limitations. Genetical genomics will provide a fresh view and has great promise to uncover new regulatory rules of NMD. We will develop novel statistical and computational methods tailored to the analysis of NMD regulation. These methods can also be broadly applied to studies of other regulatory variants. Our long-standing expertise in transcriptomics analysis, eQTL analysis, and NMD regulation places us in a unique position to accomplish the proposed project. The proposed methods meet the analysis challenges arising from transcriptomics, eQTL mapping, and RNA biology. The completion of this project will vertically advance and expand our understanding of how NMD regulates gene expression. Ultimately, such knowledge has the potential to develop NMD-based preventive and therapeutic interventions.

项目摘要 我们对废话的调节机制的理解存在根本性的差距- 介导的mRNA衰变（NMD）。最初设想为一个质量控制检查点， 并降解异常的转录本，NMD已被认为是一个转录后基因， 调节机制，以微调许多非异常内源性mRNA的表达。 然而，尽管对NMD途径有过多的生物化学表征， 对NMD的调控机制和NMD目标选择的标准知之甚少。 我们的长期目标是发展计算方法来发现基因的原理 表达调控，并探讨基因调控中的变异或缺陷如何导致 表型变异或疾病。本申请的总体目标是阐明本发明的实施例。 通过遗传基因组学对单个基因的背景依赖性NMD调控。遗传 与基因表达变化相关的变异（表达数量性状位点，eQTL） 在越来越大规模的人类研究中被编入目录，例如基因型组织 Expression（GTEx）项目。我们将利用这一前所未有的资源， NMD控制，并以系统和公正的方式发现NMD监管规则。 传统的生物化学和分子生物学方法是破解NMD的关键 机制，但进展缓慢，具有内在局限性。基因组学将提供一个 新的观点，并有很大的希望揭示新的管理规则的NMD。我们将开发 新的统计和计算方法，专门用于分析国家导弹防御系统的规定。这些 这些方法也可以广泛地应用于其它调节变体的研究。我们的长期 在转录组学分析，eQTL分析和NMD调控方面的专业知识使我们处于独特的 以完成拟议的项目。 所提出的方法满足了转录组学、eQTL 以及RNA生物学。这一项目的建成将纵向推进，扩大 我们对NMD如何调节基因表达的理解。最终，这些知识 开发基于NMD的预防和治疗干预措施的潜力。