Non-coding RNA structure change in Chronic Obstructive Pulmonary Disease

慢性阻塞性肺疾病中非编码RNA结构的变化

• 批准号: 10743413
• 负责人: Alain T Laederach
• 金额: $ 70.28万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10743413
• 关键词: 3' Untranslated Regions; 3-Dimensional; 5' Untranslated Regions; Adenosine; Adopted; Adult; Affect; Alleles; Ally; Alternative Splicing; Area; Base Pairing; Binding Proteins; Biological; Biological Assay; Blood; Candidate Disease Gene; Cations; Cell Line; Cells; Charge; Chemicals; Chemistry; Chronic Obstructive Pulmonary Disease; Code; Collection; Complex; Coupled; Data; Development; Disease; Distal; Environmental Risk Factor; Etiology; Event; Exhibits; Exons; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Transcription; Genome; Human; Introns; Luciferases; Lung; Lung diseases; Maps; Measures; Mediating; Messenger RNA; Mutation; Oligonucleotides; Open Reading Frames; Patients; Play; Poly A; Polyadenylation; Population; Positioning Attribute; Post-Transcriptional Regulation; Protein Isoforms; Proteins; Quantitative Trait Loci; RNA; RNA Probes; RNA Sequences; RNA Splicing; RNA-targeting therapy; Reporter; Research; Ribosomes; Role; Sampling; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Site; Smoker; Smoking; Structure; Technology; Tissues; Transcript; Translations; United States; Untranslated RNA; Untranslated Regions; Work; alpha 1-Antitrypsin; clinically relevant; design; disorder risk; genome wide association study; infancy; mRNA Precursor; mRNA Stability; mRNA Translation; new technology; novel; programs; protein expression; response; small molecule; technological innovation; therapeutic RNA; three-dimensional modeling; transcriptome; transcriptome sequencing; transcriptomics; translation assay; translational impact; vaping

SUMMARY Chronic obstructive pulmonary disease (COPD) is a complex genetic disease associated with over 160 genes coupled with numerous environmental factors. In most cases, the single-nucleotide polymorphisms (SNPs) most strongly associated with COPD do not alter the protein coding sequence of genes but instead map to non-coding, but often transcribed, regions of the genome, including UTRs and introns. Our collaborative work to date has focused on how 5' and 3' UTR RNA structures are affected by SNPs and has revealed that many sequence changes modulate RNA structures and alter translation of COPD-associated genes. Understanding of the interrelationships between RNA structure and gene expression is in its infancy, has primarily focused on the based-paired secondary structure of exons, and has been severely limited by our inability to fully explore RNA structure in cells. We have developed three novel chemistry-based RNA structure probing strategies that allow us to (i) investigate precursor mRNA structure in cells, (ii) identify regions in UTRs that likely adopt true higher- order tertiary structure, and (iii) determine through-space contacts in RNAs and develop three-dimensional models of their complex structures. These technologies open broad and long-term research areas into how complex RNA structures modulate gene expression and how RNA structure is changed by SNPs associated with disease. Another critical, allied development has been collection of extensive population-wide transcriptomic (RNA-seq) data of COPD patient lung and blood tissues through consortia in which we participate. Based on these transcriptomic data and their analysis, we have characterized important changes in both splicing and polyadenylation of COPD associated genes; both processing events have important consequences on gene expression. Our program also leverages substantial exploratory work that shows that RNA structure in coding sequences of genes associated with COPD modulates their translation. For this proposal, we are now in a unique position to leverage novel technologies and transcriptomic analyses to interrogate how RNA structure regulates mRNA translation of COPD-associated genes. We expect to identify RNA structures that comprise robust targets for RNA therapeutics designed to alter post-transcriptional gene regulation of protein expression. This project will ultimately reveal new principles for how RNA structure regulates protein translation and alternative splicing and will identify RNA regulatory structures in the human transcriptome associated with COPD.

概括 慢性阻塞性肺疾病（COPD）是一种与160多个基因相关的复杂遗传疾病 加上许多环境因素。在大多数情况下，单核苷酸多态性（SNP）最多 与COPD密切相关的不会改变基因的蛋白质编码顺序，而是映射到非编码， 但经常转录，基因组的区域，包括UTR和内含子。迄今为止，我们的合作工作已有 专注于5'和3'UTR RNA结构如何受SNP的影响，并揭示了许多序列 变化调节RNA结构并改变与COPD相关基因的翻译。理解 RNA结构和基因表达之间的相互关系尚处于起步阶段，主要集中在 外显子的二级结构，并且由于无法完全探索RNA而受到严重限制 细胞中的结构。我们已经开发了三种新型基于化学的RNA结构探测策略，以 我们要（i）研究细胞中的前体mRNA结构，（ii）确定UTR中可能采用真正更高的区域 第三级结构，（iii）确定RNA中的空间接触并发展三维 其复杂结构的模型。这些技术开辟了广泛和长期的研究领域 复杂的RNA结构调节基因表达以及与SNP相关的RNA结构如何改变 疾病。另一个关键的盟国发展是收集广泛的人口范围的转录组 （RNA-seq）通过我们参与的COPD患者肺和血液组织的数据。基于 这些转录组数据及其分析，我们表征了剪接和 COPD相关基因的聚腺苷酸化；两个处理事件对基因都有重要的后果 表达。我们的计划还利用了大量的探索性工作，该工作表明RNA结构在编码中 与COPD相关的基因序列调节其翻译。对于此建议，我们现在处于独特之处 利用新技术和转录组分析的位置，以询问RNA结构如何调节 COPD相关基因的mRNA翻译。我们期望识别构成强大目标的RNA结构 用于改变蛋白质表达的转录后基因调节的RNA疗法。这个项目 最终将揭示RNA结构如何调节蛋白质翻译和替代剪接的新原则 并将确定与COPD相关的人类转录组中的RNA调节结构。