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：
8586556
负责人：
Alain T Laederach
金额：
$ 35.29万
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/8586556
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.

概括慢性阻塞性肺疾病（COPD）仍然是美国死亡率的主要原因吸烟人群。有趣的是，只有15％的吸烟者发育COPD，表明有强大的吸烟者疾病的遗传成分。特定基因在内的突变，包括serpina1，编码„ - 1-抗丁硫蛋白与增加COPD的风险增加有关。基因作为DNA存在（脱氧核糖酸），RNA（核糖核酸）和蛋白质。使用新颖的计算和实验预测和验证RNA结构的技术，我们已经确定了与 mRNA的SERPINA1非编码区域中的COPD。 Ribosnitch是一个结构化元素如果特定的，疾病相关的SNP（单核苷酸），则采用替代构象的RNA 存在多态性）。我们确定了与COPD相关的突变影响mRNA未翻译区域（UTRS）的结构的SERPINA1。此外，这些非编码区具有高度多态剪接模式，我们显示的影响RNA 结构。我们建议进一步研究非编码RNA结构在COPD中的作用。具体来说，我们将开发serpina1 mRNA的高度预测模型，并确定结构和功能的突变。这将使我们能够将基因型信息与基因的调节非编码区的结构和功能。通过确定功能核能构象变化对肺和肝CEL类型基因调节的后果（在最高表达serpina1的情况下），我们将建立必要的结构/功能关系以获得对SERPINA1 mRNA在COPD中的作用的预测理解。