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.

总结 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性疾病 再加上许多环境因素。在大多数情况下，单核苷酸多态性（SNPs）最 与COPD密切相关的基因不改变基因的蛋白质编码序列，而是映射到非编码， 但通常被转录的基因组区域，包括UTR和内含子。迄今为止，我们的合作工作 重点关注5'和3' UTR RNA结构如何受到SNP的影响，并揭示了许多序列 这些变化调节RNA结构并改变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 碱基配对的二级结构的外显子，并已严重限制了我们无法充分探索RNA 细胞中的结构。我们已经开发了三种新的基于化学的RNA结构探测策略， 我们（i）研究细胞中的前体mRNA结构，（ii）鉴定UTR中可能采用真正的高表达的区域， 顺序的三级结构，和（iii）确定通过空间接触的RNA和发展三维 其复杂结构的模型。这些技术开辟了广泛而长期的研究领域， 复杂的RNA结构调节基因表达，以及RNA结构如何被与 疾病另一个关键的、相关的发展是收集了广泛的人群范围内的转录组学数据， 通过我们参与的联合体获得的COPD患者肺和血液组织的RNA测序（RNA-seq）数据。基于 通过这些转录组学数据及其分析，我们已经表征了剪接和 COPD相关基因的多聚腺苷酸化;两种处理事件对基因表达具有重要影响。 表情我们的项目还利用了大量的探索性工作，这些工作表明编码中的RNA结构 与COPD相关的基因序列调节它们的翻译。对于这项提议，我们现在处于一个独特的 利用新技术和转录组学分析来研究RNA结构如何调节 COPD相关基因的mRNA翻译。我们希望能够识别出包含强大靶标的RNA结构 用于设计改变蛋白质表达的转录后基因调控的RNA治疗。这个项目 将最终揭示RNA结构如何调节蛋白质翻译和选择性剪接的新原理 并将鉴定与COPD相关的人类转录组中的RNA调控结构。