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: 10413012
• 负责人: Alain T Laederach
• 金额: $ 52.02万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413012
• 关键词: 5' Untranslated Regions; Affect; Alternative Splicing; American; Area; Chronic Obstructive Pulmonary Disease; Complex; Computer Models; Data; Development; Disease; Down-Regulation; Elements; Exons; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genome; Genomic approach; Genomics; Goals; Human; Human Genome; Laboratories; Lead; Liver; Location; Lung; Maps; Measures; Mediating; Messenger RNA; Modeling; Molecular; Mutate; Nucleotides; Open Reading Frames; Outcome; Participant; Protein Biosynthesis; Protein Isoforms; Proteins; RNA; RNA Splicing; Regulation; Resolution; Resources; Ribosomes; Risk Factors; Scanning; Severity of illness; Site; Smoking; Structural Models; Structure; Testing; Tissues; Transcript; Translating; Translations; Untranslated RNA; Untranslated Regions; Up-Regulation; Variant; Work; base; causal variant; computer framework; design; differential expression; experimental study; genetic association; genetic variant; mRNA Expression; mortality; novel; precision medicine; programs

SUMMARY Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality in the developed world. Smoking is an important risk factor for the disease, but genetics determine outcome and disease severity. A significant and broad challenge in establishing the causal molecular mechanism from genetic association data is the fact that a majority of COPD-associated variants map to non-coding regions of the human genome. One of the genes strongly associated with COPD is SERPINA1, which encodes the a-1 antitrypsin protein. The SERPINA1 gene is remarkably complex: It has eleven splice variants, all of which change the 5'-untranslated region (5'-UTR) without altering the sequence of the encoded protein. We found that translation efficiencies of the mRNAs varied by orders of magnitude due to the strengths of upstream RNA structure and of open reading frames (uORFs). uORFs are found in roughly 50% of human genes and tend to function to reduce translation of the downstream gene but, other than this observation, are poorly understood mechanistically. We have developed and parameterized a structure-based leaky scanning model of translation that considers alternative splicing, uORF Kozak sequence strength, the RNA structure at the initiation site of uORFs, and the efficiency of translation of the primary open reading frame. We propose in our first aim to define how RNA structure and alternative splicing control expression of a-1 antitrypsin and extend this approach to two other COPD-associated genes. In our second aim we will comprehensively characterize the RNA structural elements in the SERPINA1 mRNA 5'-UTRs and in two other COPD-related mRNAs that control translation efficiency, without and with uORFs. These experiments will establish accurate and broadly impactful frameworks to define the RNA structural features that modulate translation efficiency in 5'-UTRs and will refine ribosomal leaky scanning models to better predict tissue-specific expression of COPD-associated proteins.

总结 慢性阻塞性肺病（COPD）是发达国家的主要死亡原因。吸烟 是疾病的一个重要危险因素，但遗传学决定了结果和疾病的严重程度。显著 从遗传关联数据中建立因果分子机制的广泛挑战是， 大多数COPD相关的变异体映射到人类基因组的非编码区。的基因之一 与COPD密切相关的是SERPINA 1，它编码α-1抗胰蛋白酶蛋白。SERPINA 1基因 它非常复杂：它有11个剪接变体，所有这些变体都会改变5 '-非翻译区（5'-UTR）。 而不改变编码蛋白质的序列。我们发现mRNA的翻译效率不同， 由于上游RNA结构和开放阅读框（uORF）的强度， uORF存在于大约50%的人类基因中，并且倾向于起到减少下游转录的作用。 基因，但除了这一观察，很少了解机械。我们已经开发并 参数化了一个基于结构的漏扫描翻译模型，该模型考虑了选择性剪接uORF Kozak序列强度、uORF起始位点处的RNA结构以及UORF的翻译效率是影响UORF的翻译效率的主要因素。 主要开放式阅读框架。我们的第一个目标是定义RNA结构和选择性剪接 控制α-1抗胰蛋白酶的表达，并将这种方法扩展到其他两个COPD相关基因。在我们 第二个目标是，我们将全面表征SERPINA 1 mRNA 5 '-UTR中的RNA结构元件 以及另外两种控制翻译效率的COPD相关mRNA，不含和含uORF。这些 实验将建立准确和广泛的影响框架，以定义RNA结构特征， 调节5 '-UTR的翻译效率，并将改进核糖体泄漏扫描模型，以更好地预测 COPD相关蛋白的组织特异性表达。