Non-coding RNA structure change in Chronic Obstructive Pulmonary Disease

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%的吸烟者会患上COPD，这表明这种疾病有很强的遗传因素。包括编码1- 1-抗胰蛋白酶的SERPINA 1在内的特定基因的突变与发展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结构的新的计算和实验技术，我们已经在mRNA的SERPINA 1非编码区中确定了与COPD相关的“RiboSNitch”。RiboSNitch是RNA中的结构化元件，如果存在特定的疾病相关SNP（单核苷酸多态性），则其采用替代构象。我们在SERPINA 1的非编码区发现了与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的剪接模式，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SERPINA 1 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SERPINA 1表达最高）中基因调控的功能后果，我们将建立必要的结构/功能关系，以预测SERPINA 1 mRNA在COPD中的作用。 公共卫生相关性：本研究旨在探讨慢性阻塞性肺疾病（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和增加COPD风险的基因非翻译区（UTRS）突变。我们将建立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COPD易感性的能力。

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.