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

基本信息

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
项目类别：
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&apos Untranslated Regions 3-Dimensional 5&apos 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

项目摘要

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性疾病再加上众多的环境因素。在大多数情况下，单核苷酸多态性（SNP）最与慢性阻塞性肺病密切相关的基因不会改变蛋白质编码序列，而是映射到非编码序列，但通常转录的是基因组区域，包括 UTR 和内含子。迄今为止，我们的合作工作已经重点研究 5' 和 3' UTR RNA 结构如何受到 SNP 的影响，并揭示了许多序列变化调节 RNA 结构并改变 COPD 相关基因的翻译。的理解 RNA结构和基因表达之间的相互关系还处于起步阶段，主要集中在基于外显子配对的二级结构，并且由于我们无法充分探索 RNA 而受到严重限制细胞内的结构。我们开发了三种基于化学的新型 RNA 结构探测策略，允许我们 (i) 研究细胞中的前体 mRNA 结构，(ii) 识别 UTR 中可能采用真正更高水平的区域排序三级结构，以及 (iii) 确定 RNA 中的空间接触并开发三维结构其复杂结构的模型。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与相关的 SNP 如何改变 RNA 结构疾病。另一个重要的联合发展是收集广泛的全人群转录组数据通过我们参与的联盟获得 COPD 患者肺和血液组织的 (RNA-seq) 数据。基于通过这些转录组数据及其分析，我们描述了剪接和转录的重要变化 COPD 相关基因的多聚腺苷酸化；这两个加工事件都对基因产生重要影响表达。我们的计划还利用了大量的探索性工作，表明编码中的 RNA 结构与慢性阻塞性肺病相关的基因序列调节其翻译。对于这个提案，我们现在处于一个独特的阶段利用新技术和转录组分析来探究 RNA 结构如何调节 COPD 相关基因的 mRNA 翻译。我们期望鉴定出包含稳健靶标的 RNA 结构用于旨在改变蛋白质表达的转录后基因调控的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 调节结构。