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The Mechanisms and Regulatory Networks of Alternative Splicing in Drosophila

果蝇选择性剪接的机制和调控网络

基本信息

批准号：
7918448
负责人：
Brenton R. Graveley
金额：
$ 10.52万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-18 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7918448
关键词：
Accounting Alternative Splicing Antigen Targeting Ataxia Autoimmune Diseases Binding Biochemical Biochemical Genetics Biochemistry Bioinformatics Biological Models Boxing Collection Complement Cultured Cells Defect Development Drosophila genome Drosophila genus Eukaryota Exons Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genome Genomics Goals Health Homologous Gene Human Lead Logic Messenger RNA Modeling Myoclonus Opsoclonus Organism Pattern Play Process Proteins RNA RNA Interference RNA Splicing RNA-Binding Proteins Regulation Regulator Genes Research Personnel Research Proposals Role Site Spliceosome Assembly Pathway Spliceosomes Staging Transcriptional Regulation Translations Work design genome-wide human disease insight interest mRNA Precursor programs protein function protein protein interaction research study

项目摘要

DESCRIPTION (provided by applicant): Intricate gene regulatory networks direct the development of multi-cellular eukaryotes. Although transcription regulation is the best understood mechanism by which these networks are controlled, it has recently become clear that alternative splicing is an equally important regulatory mechanism. Despite the fact that the majority of eukaryotic genes encode pre-mRNAs that are alternatively spliced (at least 65% of human genes), very few splicing regulatory factors have been identified, and the target genes that are controlled by specific splicing regulators are largely unknown. Alternative splicing is primarily thought to be regulated by auxiliary splicing factors - proteins that are not core components of the spliceosome. Auxiliary splicing factors function by binding to the pre-mRNA where they modulate the association of the spliceosome with the regulated splice sites. Recent work from our group and others, however, suggests that components of the general splicing machinery may also play important roles in regulating alternative splicing. This may in part account for the apparent discrepancy between the numbers of known splicing regulators and regulatory targets. The goals of this research proposal are to identify proteins that regulate alternative splicing and their regulatory targets on a genome-wide level, and to determine the biochemical mechanisms by which these proteins regulate alternative splicing using Drosophila melaongaster as a model system. We will first perform microarray experiments to identify alternatively spliced exons that are regulated by the entire complement of RNA binding proteins encoded by the Drosophila genome and to build a model of the splicing regulatory networks in Drosophila. These experiments will be complemented by a combination of biochemical, genetic, genomic, and bioinformatics experiments designed to determine the mechanisms by which both auxiliary and general splicing factors function to control alternative splicing. Together these experiments will provide tremendous insight into the mechanisms of alternative splicing. Given that the proteins involved in regulating alternative splicing in Drosophila and humans are similar, that a number of human diseases are caused by defects in the normal patterns of alternative splicing, and that the human homologs of many of the proteins we will be studying have been implicated in human diseases, it is likely that the discoveries we make will be of direct relevance to human health.

描述（由申请人提供）：复杂的基因调控网络指导多细胞真核生物的发育。虽然转录调控是控制这些网络的最好理解的机制，但最近已经清楚的是，选择性剪接是一种同样重要的调控机制。尽管事实上大多数真核基因编码选择性剪接的前体mRNA（至少65%的人类基因），但已鉴定的剪接调控因子很少，并且由特定剪接调控因子控制的靶基因在很大程度上是未知的。选择性剪接主要被认为是由辅助剪接因子调节的，这些蛋白质不是剪接体的核心成分。辅助剪接因子通过与前体mRNA结合来发挥作用，在前体mRNA中它们调节剪接体与受调节的剪接位点的结合。然而，我们小组和其他人最近的工作表明，一般剪接机制的组成部分也可能在调节选择性剪接中发挥重要作用。这可能部分解释了已知剪接调节子和调节靶点的数量之间的明显差异。本研究的目标是在全基因组水平上鉴定调节选择性剪接的蛋白质及其调节靶点，并以果蝇为模型系统，确定这些蛋白质调节选择性剪接的生化机制。我们将首先进行微阵列实验，以确定由果蝇基因组编码的RNA结合蛋白的整个补体调控的选择性剪接外显子，并建立果蝇中剪接调控网络的模型。这些实验将通过生物化学，遗传学，基因组学和生物信息学实验的组合来补充，这些实验旨在确定辅助和一般剪接因子控制选择性剪接的机制。这些实验一起将提供巨大的洞察机制的选择性剪接。考虑到参与调节果蝇和人类选择性剪接的蛋白质是相似的，许多人类疾病是由正常选择性剪接模式的缺陷引起的，而且我们将要研究的许多蛋白质的人类同源物与人类疾病有关，我们的发现很可能与人类健康直接相关。