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的差距 - 介导的mRNA衰变（NMD）。最初被认为是质量控制检查站 NMD和降低异常笔录已被视为转录后基因 调节机制以微调许多无常见内源mRNA的表达。 然而，尽管在NMD途径上有大量的生化表征，但 NMD调控的机制和NMD目标选择的标准知之甚少。 我们的长期目标是开发计算方法来发现基因的原理 表达调节并探索基因调节中的变异或缺陷如何导致 表型变异或疾病。该应用的总体目的是阐明 通过遗传基因组学对各个基因的NMD调节。遗传 与基因表达变化相关的变体（表达定量性状基因座，eqtls） 正在越来越大的人类研究中分类，例如基因型 - 组织 表达（GTEX）项目。我们将利用这种前所未有的资源来剖析 NMD控制并以系统性和无偏见的方式发现NMD监管规则。 传统的生化和分子方法对于破译NMD至关重要 机制但固有局限性的进展缓慢。遗传基因组学将提供 新的视图，并有很大的希望，可以揭示NMD的新监管规则。我们将发展 针对NMD调节分析的新型统计和计算方法。这些 方法也可以广泛应用于其他调节变体的研究。我们的长期 转录组学分析，EQTL分析和NMD调节方面的专业知识使我们处于独特的状态 完成拟议项目的位置。 提出的方法符合转录组学引起的分析挑战，eqtl 映射和RNA生物学。该项目的完成将垂直进步并扩展 我们对NMD如何调节基因表达的理解。最终，这样的知识具有 开发基于NMD的预防和治疗干预措施的潜力。