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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.

总结