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: 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
• 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' 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

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 慢性阻塞性肺疾病（COPD）仍然是美国死亡的主要原因。 吸烟人口。有趣的是，只有15%的吸烟者患上COPD，这表明有很强的 该疾病的遗传成分。包括SERPINA 1在内的特定基因突变，该基因编码 1-抗胰蛋白酶，与发展COPD的风险增加有关。基因以DNA（脱氧）形式存在 核糖核酸）、RNA（核糖核酸）和蛋白质。使用新的计算和实验 通过预测和验证RNA结构的技术，我们已经确定了一种与RNA结构相关的“RiboSNitch”。 COPD中SERPINA 1 mRNA的非编码区。RiboSNitch是一个结构化元素， 如果特定的疾病相关的SNP（单核苷酸） 多态性（Polymorphism）。我们发现了与COPD相关的基因突变， SERPINA 1影响mRNA非翻译区（UTRS）的结构。而且这些 非编码区具有高度多态性的剪接模式，我们已经证明， 结构我们建议进一步研究非编码RNA结构在COPD中的作用。具体地说， 我们将开发SERPINA 1 mRNA的高度预测模型，并确定 结构和功能上的突变。这将使我们能够将基因型信息与 基因调控非编码区的结构和功能。通过确定函数 RiboSNitch构象变化对肺和肝细胞类型基因调控的影响 （其中SERPINA 1表达最高），我们将建立必要的结构/功能 关系，以获得对SERPINA 1 mRNA在COPD中的作用的预测性理解。