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Alternative pre-mRNA Splicing in Drosophila

果蝇中的选择性前 mRNA 剪接

基本信息

批准号：
8605198
负责人：
DONALD C RIO
金额：
$ 39.62万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
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：
2012-05-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8605198
关键词：
5&apos Splice Site Address Affect Alternative Splicing Alzheimer&apos s Disease Base Pairing Binding Binding Sites Biochemical Bioinformatics Biological Assay Cell Nucleus Cells ChIP-seq Data Defect Disease Drosophila genome Drosophila genus Elements Event Functional RNA Funding Gene Duplication Gene Expression Gene Mutation Genes Genetic Genome Genomics Grant Health Heterogeneous-Nuclear Ribonucleoprotein Group A-B Homologous Gene Human In Vitro Informatin Introns Investigation Lead Learning Link Malignant Neoplasms Methods MicroRNAs Modeling Mus Myotonic Dystrophy Organism Pathway interactions Pattern Phosphorus Process Property Protein Splicing Protein Structure Initiative Proteins Proteome Proteomics RNA RNA Binding RNA Interference RNA Processing RNA Splicing RNA-Binding Proteins RNA-Protein Interaction Recruitment Activity Regulation Regulatory Element Repression Repressor Proteins Research Role Site Small RNA Split Genes System Testing Testis Therapeutic Intervention Tissues Transcript Transcriptional Silencer Elements U1 Small Nuclear Ribonucleoprotein Work abstracting cell type genome-wide genome-wide analysis human disease in vivo insight mRNA Precursor novel paralogous gene protein protein interaction

项目摘要

DESCRIPTION (provided by applicant): PROJECT SUMMARY / ABSTRACT Alternative pre-mRNA splicing in Drosophila. D. Rio - PI Alternative pre-mRNA splicing is an important mechanism for regulating gene expression in metazoans. Indeed, RNA processing is a conduit through which genomic information is transferred to proteomic information. Because most eukaryotic genes are split and have the potential for alternative splicing, a dramatic increase in proteomic diversity among cells, tissues and organisms is a direct consequence of alternative splicing. In fact, it is now recognized that 30-40% of the known human and mouse disease gene mutations affect the splicing process. Thus, understanding how introns are recognized and how patterns of alternative splicing are set up may allow therapeutic intervention. Splicing silencers are a major type of RNA control element generating tissue- or cell type-specific splicing patterns in metazoans. Our previous work has focused on characterization of the tissue-specific Drosophila P element splicing silencer element. Recent work from our group has focused on tissue-specific regulation of alternative splicing and how the action of hnRNP proteins, PSI and the hnRNP A/B family proteins, hrp48, 40, 38 and 36 results in splicing silencer function. We wish to extend these studies to investigate the function of a Drosophila paralog of U2AF, called LS2, that functions as a splicing repressor. Building on previous R21 funding, we will continue investigations of the microRNA pathway protein, Ago-2, in alternative splicing pathways. Finally, using a variety of approaches, we want to identify and functionally characterize new cellular splicing silencers that are controlled by multiple splicing factors. One advantage this proposal has is the small genome size and well-annotated Drosophila genome that allows a comprehensive analysis of both alternative splicing patterns and the genome-wide distribution of RNA binding proteins. Because most eukaryotic genes are split and have the potential for alternative splicing, increased proteomic diversity among cells, tissues and organisms is a direct consequence of alternative splicing. Because the protein factors involved in controlling patterns of alternative splicing have homologs in humans and like humans Drosophila has extensive alternative splicing, results obtained in this system will have direct relevance and application to human health.

描述（由申请人提供）：果蝇前体mRNA的选择性剪接。D. Rio-PI前体mRNA选择性剪接是后生动物基因表达调控的重要机制。事实上，RNA加工是基因组信息转移到蛋白质组信息的管道。由于大多数真核基因是分裂的，并且具有选择性剪接的潜力，因此细胞、组织和生物体中蛋白质组多样性的急剧增加是选择性剪接的直接结果。事实上，现在人们认识到，30-40%的已知人类和小鼠疾病基因突变会影响剪接过程。因此，了解内含子是如何被识别的，以及选择性剪接的模式是如何建立的，可能会允许治疗干预。剪接沉默子是后生动物中产生组织或细胞类型特异性剪接模式的主要类型的RNA控制元件。我们以前的工作集中在组织特异性果蝇P元件剪接沉默元件的表征。我们小组最近的工作集中在选择性剪接的组织特异性调节以及hnRNP蛋白、PSI和hnRNP A/B家族蛋白、hrp 48、40、38和36的作用如何导致剪接沉默子功能。我们希望扩展这些研究，以调查的功能，果蝇paradigm的U2 AF，称为LS 2，作为一个剪接阻遏物的功能。在之前的R21资助的基础上，我们将继续研究选择性剪接途径中的microRNA途径蛋白Ago-2。最后，使用各种方法，我们希望确定和功能特性的新的细胞剪接沉默，由多种剪接因子控制。这个建议的一个优点是小的基因组大小和注释良好的果蝇基因组，允许全面分析的选择性剪接模式和RNA结合蛋白的全基因组分布。由于大多数真核基因是分裂的，并具有选择性剪接的潜力，因此细胞、组织和生物体之间蛋白质组多样性的增加是选择性剪接的直接结果。由于参与控制选择性剪接模式的蛋白质因子在人类中具有同源物，并且与人类一样，果蝇具有广泛的选择性剪接，因此在该系统中获得的结果将与人类健康直接相关并应用于人类健康。