Alternative RNA splicing and protein products in leukemia outcome (PQ11)

白血病结局中的替代 RNA 剪接和蛋白质产物 (PQ11)

• 批准号: 8677825
• 负责人: SCOTT A. NESS
• 金额: $ 57.86万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-08 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677825
• 关键词: Acute Lymphocytic Leukemia; Address; Affect; Alternative Splicing; B-Cell Acute Lymphoblastic Leukemia; Bioinformatics; Biological; Biological Assay; Child; Childhood; Childhood Leukemia; Chronic Lymphocytic Leukemia; Data; Data Set; Development; Disease; Enzymes; Event; Exons; Gene Expression; Gene Expression Profiling; Genes; Goals; Intervention; Knowledge; Length; Link; Measures; Messenger RNA; Methodology; Methods; Molecular; Noise; Normal Cell; Oncogenes; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Population; Process; Proteins; Protocols documentation; RNA; RNA Processing; RNA Sequences; RNA Splicing; Regulation; Role; Sampling; Signal Pathway; Structure; Survival Rate; Testing; Therapeutic; Time; Transcript; Variant; cell transformation; clinically significant; cohort; combinatorial; experience; genetic regulatory protein; genome-wide; high risk; improved; innovation; knock-down; leukemia; next generation; novel; progenitor; protein profiling; research study; standard care; treatment strategy; tumor; tumorigenesis

DESCRIPTION (provided by applicant): This application will address NCI Provocative Question 11: How do changes in RNA processing contribute to tumor development? Tumors and leukemias have dramatically increased levels of aberrant RNA splicing, which generates a large population of transcripts that could encode variant proteins. This increased complexity of RNA products could be due to "noisy" splicing that is increased in transformed cells, but has no functional consequence. Alternatively, the variant RNAs and the proteins they encode could actively contribute to the transformed phenotype. Increased levels of alternative splicing in tumors leads to the expression of transcripts that are too numerous to test individually, for example by over-expression or knock down experiments. Furthermore, if the importance of the variant proteins is due to a mass action or combinatorial effect, then assessing their importance individually will not suffice. Our hypothesis is that if the increased alternative splicing exhibitd by tumors or leukemias contributes to tumor development, then determining the predicted expression levels of protein variants encoded by the alternatively spliced RNAs will be more informative, and will correlate with outcome better than simply measuring the RNA levels. If the products of alternative splicing play no significant biological role, then determining which proteins are produced by the alternatively spliced RNAs will offer no additional advantage in predicting outcome. We will apply an innovative next-generation RNA sequencing approach to the analysis of alternative RNA splicing in a large group of high risk childhood B- progenitor Acute Lymphocytic Leukemia (ALL) samples. Despite recent improvements in the treatments for B- ALL, this high risk cohort represents a group of patients for whom few good treatment options exist. Our approach will produce structural information over the entire length of more than 99% of expressed transcripts, allowing us to analyze gene expression, RNA splicing and the populations of protein variants that are predicted to be produced in each sample. Comparing these data sets will allow us to answer the Provocative Question and to determine whether increased levels of alternative RNA splicing are important in the development of B- progenitor ALL. The alternative splicing machinery contains many poorly characterized enzymes and regulatory proteins. If increased alternative splicing is found to play a role in tumor development these proteins will represent novel potential targets for the development of new drugs or interventions.

描述（由申请人提供）：此申请将解决NCI挑衅性问题11：RNA处理的变化如何有助于肿瘤的发展？肿瘤和白血病显着增加了异常RNA剪接水平，这会产生大量的转录本，这些转录本可以编码变异蛋白。 RNA产物的复杂性提高可能是由于转化细胞中增加的“嘈杂”剪接，但没有功能性后果。另外，它们编码的变体RNA及其蛋白质可以积极促进转化的表型。肿瘤中替代剪接水平的增加导致转录本的表达太多，无法单独测试，例如通过过表达或敲击实验。此外，如果变体蛋白的重要性是由于质量作用或组合效应引起的，那么单独评估其重要性就不够。我们的假设是，如果增加的替代剪接表现为肿瘤或白血病有助于肿瘤的发展，那么确定由替代剪接的RNA编码的蛋白质变异的预测表达水平将更具信息性，并且将更具信息性，并且将与结果相关，而不是简单地测量RNA水平。如果替代剪接的产物没有重要的生物学作用，那么确定哪些蛋白质是由剪接的RNA产生的，将在预测结果方面没有其他优势。我们将在一大批高风险儿童B-祖细胞急性淋巴细胞性白血病（所有）样品中应用创新的下一代RNA测序方法来分析替代RNA剪接的分析。尽管B- ALL的治疗方法最近有所改善，但这种高风险队列代表了一群很少有好治疗选择的患者。我们的方法将在超过99％表达的转录本的整个长度中产生结构信息，从而使我们能够分析每个样品中预测会产生的基因表达，RNA剪接和蛋白质变体的种群。比较这些数据集将使我们能够回答挑衅性的问题，并确定增加替代RNA剪接水平是否在B-祖细胞的发展中很重要。替代剪接机器包含许多特征较差的酶和调节蛋白。如果发现增加的替代剪接在肿瘤发育中起作用，那么这些蛋白质将代表开发新药或干预措施的新型潜在靶标。