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）：该申请将解决 NCI 的挑衅性问题 11：RNA 加工的变化如何促进肿瘤的发展？肿瘤和白血病的异常RNA剪接水平显着增加，从而产生大量可编码变异蛋白的转录本。 RNA 产物复杂性的增加可能是由于转化细胞中“嘈杂”剪接的增加，但没有功能性后果。或者，变异的 RNA 及其编码的蛋白质可以积极促进转化的表型。肿瘤中选择性剪接水平的增加导致转录物的表达过多而无法单独测试，例如通过过度表达或敲低实验。此外，如果变异蛋白的重要性是由于集体作用或组合效应造成的，那么单独评估它们的重要性是不够的。我们的假设是，如果肿瘤或白血病表现出的选择性剪接增加有助于肿瘤的发展，那么确定选择性剪接 RNA 编码的蛋白质变体的预测表达水平将提供更多信息，并且与结果的相关性比简单测量 RNA 更好水平。如果选择性剪接的产物不发挥重要的生物学作用，那么确定选择性剪接的 RNA 产生哪些蛋白质将不会在预测结果方面提供额外的优势。我们将应用创新的下一代 RNA 测序方法来分析大量高风险儿童 B 祖细胞急性淋巴细胞白血病 (ALL) 样本中的选择性 RNA 剪接。尽管 B-ALL 的治疗方法最近有所改进，但这个高风险队列代表了一组几乎不存在良好治疗选择的患者。我们的方法将产生超过 99% 的表达转录本的全长结构信息，使我们能够分析基因表达、RNA 剪接以及预测每个样本中产生的蛋白质变体群体。比较这些数据集将使我们能够回答这个令人兴奋的问题，并确定选择性 RNA 剪接水平的增加对于 B 祖细胞 ALL 的发展是否重要。选择性剪接机制包含许多特征不明的酶和调节蛋白。如果发现增加的选择性剪接在肿瘤发展中发挥作用，这些蛋白质将代表新药物或干预措施开发的新的潜在靶点。