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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：
8403664
负责人：
Alain T Laederach
金额：
$ 34.28万
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 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403664
关键词：
5&apos Untranslated Regions A549 Accounting Adopted Affect Algorithms Alternative Splicing Biological Assay Blood capillaries Cell Culture Techniques Cell Line Chronic Obstructive Airway Disease Code Collaborations Communities Complex Computer Analysis Computer Simulation Disease Disease Association Elasticity Functional RNA Gene Expression Regulation Genes Genetic Genome Goals Hepatocyte Human Indium Individual Liver Luciferases Lung Maps Messenger RNA Molecular Molecular Conformation Mutation Nature Nucleotides Obstruction Odds Ratio Pattern Population Predisposition Protein C Inhibitor Proteins Pulmonary Emphysema RNA RNA Splicing Regulatory Element Reporter Reporting Research Personnel Resolution Risk Role Single Nucleotide Polymorphism Single Nucleotide Polymorphism Map Smoker Smoking Structure Structure of parenchyma of lung Structure-Activity Relationship System Techniques Technology Testing Translations Untranslated Regions Validation Western World base capillary computerized tools computing resources experience genome wide association study improved mRNA Precursor mortality novel predictive modeling research study small molecule

项目摘要

Summary Chronic Obstructive Pulmonary Disease (COPD) remains a leading cause of mortality in the U.S. smoking population. Interestingly, only 15% of smokers develop COPD indicating that there is a strong genetic component to the disease. Mutations in specific genes including SERPINA1, which encodes ¿- 1-antitrypsin, are associated with increased risk of developing COPD. Genes exist as DNA (deoxy ribonucleic acid), RNA (ribonucleic acid) and proteins. Using novel computational and experimental techniques that predict and validate RNA structure, we have identified a "RiboSNitch" associated with COPD in the SERPINA1 non-coding region of the mRNA. A RiboSNitch is a structured element in an RNA that adopts an alternative conformation if a specific, disease-associated SNP (Single Nucleotide Polymorphism) is present. We identified mutations associated with COPD in non-coding regions of SERPINA1 that affect the structure of the mRNA untranslated regions (UTRS). Furthermore, these non-coding regions have highly polymorphic splicing patterns, which we have shown affect RNA structure. We propose to further investigate the role of non-coding RNA structure in COPD. Specifically, we will develop highly predictive models of the SERPINA1 mRNA and determine the efects of mutations on structure and function. This will enable us to correlate genotypic information with the structure and function of the regulatory non-coding regions of genes. By determining the functional consequences of RiboSNitch conformational changes on gene regulation in lung and liver cel types (where SERPINA1 is most highly expressed), we will establish the necessary structure/function relationships to obtain a predictive understanding of the role of SERPINA1 mRNA in COPD.

总结