Computational and experimental modeling of RNA Splicing

RNA 剪接的计算和实验模型

• 批准号: 7896414
• 负责人: MICHAEL Q ZHANG
• 金额: $ 35.8万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-13 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896414
• 关键词: Access to Information; Address; Affect; Algorithms; Alternative Splicing; BRCA1 gene; Binding Sites; Biological Assay; Collaborations; Communities; Computer Simulation; Data Set; Databases; Dependence; Dependency; Development; Elements; Enhancers; Eukaryotic Cell; Event; Exons; Experimental Models; Expressed Sequence Tags; Gene Expression Regulation; Genes; Goals; Human; Internet; Introns; Lead; Literature; Methods; Modeling; Molecular; Online Systems; Pattern; Play; Positioning Attribute; Property; Protein Isoforms; Proteins; RNA Splicing; Regulation; Regulatory Element; Relative (related person); Research; Resources; Role; Services; Site; Split Genes; System; Testing; Tissue-Specific Splicing; Tissues; Validation; cell type; combinatorial; computerized tools; hnRNP A1; hnRNP protein A1; human disease; improved; mRNA Precursor; mathematical model; mutant

DESCRIPTION (provided by applicant): The discovery that eukaryotic genes are "split" into exons and introns has had enormous implications for our understanding of gene expression and regulation. It is now recognized that more than half of human genes are expressed via alternative splicing, frequently in specific spatial/temporal patterns. Alternative splicing plays a fundamental role in determining the specialized properties of differentiated eukaryotic cell types during normal development, and misregulation of splicing is increasingly recognized as being responsible for many human diseases. The main goal of this project is to form a cutting-edge research team comprising computational and experimental molecular biologists to model two biologically important problems: How do c/s-elements regulate pre-mRNA splicing? How do they affect splice-site selection? To address these problems, the following specific aims are proposed. 1) To mathematically and experimentally model the dependency of pre-mRNA splicing activity upon SR protein- and hnRNP A1- dependent ESEs/ESSs in a few well defined systems. 2) To study the dependency of tissue-specific alternative splicing on c/s-elements and frans-acting splicing factors. 3) To improve and extend our web-based ESEfinder capability and service by including more enhancer and silencer motifs into the database and by implementing more computational tools for the user community. Our approach is a combination Of mathematical modeling and experimental testing, using minigene constructs and functional pre-mRNA splicing assays. This close collaboration between computational and experimental molecular biologists is expected to lead to a better understanding of the mechanism of pre- mRNA splicing regulation, as well as to improved public access to information about alternative splicing.

描述（由申请人提供）：发现真核基因被“分为”外显子和内含子的发现对我们对基因表达和调节的理解具有巨大的意义。现在已经认识到，超过一半的人类基因是通过替代剪接表达的，通常是在特定的空间/时间模式中表达的。替代剪接在正常发育过程中确定分化真核细胞类型的专业特性，并且剪接的不正体被越来越被认为是许多人类疾病负责的基本作用。该项目的主要目标是组成一个尖端的研究团队，其中包括计算和实验性分子生物学家，以模拟两个在生物学上重要的问题：C/S元素如何调节前MRNA剪接？它们如何影响接头选择？为了解决这些问题，提出了以下特定目标。 1）在数学上和实验上对MRNA剪接活性对SR蛋白质和HNRNP A1-依赖性ESE/ESS的依赖性在一些定义明确的系统中。 2）研究组织特异性替代剪接对C/S元素和frans作用剪接因子的依赖性。 3）通过在数据库中包括更多的增强器和消音器图案，并为用户社区实施更多的计算工具，以改善和扩展我们的基于Web的ESEFINDER功能和服务。我们的方法是使用微型构建体和功能性mRNA剪接测定法的数学建模和实验测试的组合。预计计算和实验分子生物学家之间的这种密切合作有望更好地理解MRNA剪接调节的机制，并改善了公众访问有关替代剪接信息的信息。