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：
8218425
负责人：
Alain T Laederach
金额：
$ 36.01万
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/8218425
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

DESCRIPTION (provided by applicant): 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- 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. PUBLIC HEALTH RELEVANCE: We propose to investigate the role of RNA (Ribonucleic Acid) structural changes in the non-coding regions of Chronic Obstructive Pulmonary Disease (COPD) associated genes. Specifically, we have identified mutations in the untranslated regions (UTRS) of genes that control the elasticity of lung tissue and increase the risk of developing COPD. We will build experimentally validated computational models that will predict the effects of any mutation on these genes and thus improve our ability to determine COPD predisposition based on genetic sequence.

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）仍然是美国吸烟人群死亡的主要原因。有趣的是，只有 15% 的吸烟者患有慢性阻塞性肺病，这表明该疾病有很强的遗传因素。包括编码 1-1-抗胰蛋白酶的 SERPINA1 在内的特定基因突变与罹患 COPD 的风险增加有关。基因以DNA（脱氧核糖核酸）、RNA（核糖核酸）和蛋白质的形式存在。使用预测和验证 RNA 结构的新颖计算和实验技术，我们在 mRNA 的 SERPINA1 非编码区中鉴定出了与 COPD 相关的“RiboSNitch”。 RiboSNitch 是 RNA 中的一个结构元件，如果存在与疾病相关的特定 SNP（单核苷酸多态性），它会采用替代构象。我们在 SERPINA1 非编码区中发现了与 COPD 相关的突变，这些突变影响 mRNA 非翻译区 (UTRS) 的结构。此外，这些非编码区具有高度多态性剪接模式，我们已经证明这会影响 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，并确定突变对结构和功能的影响。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相关联。通过确定 RiboSNitch 构象变化对肺和肝细胞类型（其中 SERPINA1 表达最高）基因调控的功能影响，我们将建立必要的结构/功能关系，以获得对 SERPINA1 mRNA 在 COPD 中的作用的预测性了解。公共健康相关性：我们建议研究慢性阻塞性肺病 (COPD) 相关基因非编码区 RNA（核糖核酸）结构变化的作用。具体来说，我们已经确定了控制肺组织弹性并增加患慢性阻塞性肺病风险的基因非翻译区 (UTRS) 的突变。我们将建立经过实验验证的计算模型，预测任何突变对这些基因的影响，从而提高我们根据基因序列确定慢性阻塞性肺病易感性的能力。