Genomic Measurement of Alternative Splicing

选择性剪接的基因组测量

基本信息

批准号：
8208140
负责人：
Manuel Ares
金额：
$ 45.11万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
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：
2009-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8208140
关键词：
Address Affect Alternative Splicing Cell Differentiation process Cells Cellular biology Collaborations Complex Complex Mixtures Data Analyses Databases Development Disease Eukaryota Event Exons Funding Gene Expression Gene Expression Regulation Genes Genome Genomics Glues Goals Grant Health Heart Homeostasis Human Inborn Genetic Diseases Individual Inherited Knockout Mice Laboratories Laboratory Study Lead Link Malignant Neoplasms Measurement Measures Messenger RNA Methods Microarray Analysis Modeling Monoclonal Antibody R24 Mus Muscle Muscular Dystrophies Mutation Neuronal Differentiation Neurons Nucleic Acid Hybridization Nucleic Acids Pathway interactions Pattern Printing Process Protein Isoforms Proteins RNA Splicing Regulation Regulatory Element Regulatory Pathway Research Personnel Source System Technology Technology Transfer Testing Work cost effective database design density design gene function genome-wide human disease improved instrument interest mRNA Precursor neuromuscular system novel strategies programs research study stem cell biology

项目摘要

DESCRIPTION (provided by applicant): Alternative splicing is a key process in the control of mammalian gene expression and a major source of protein diversity. Errors in splicing regulation are implicated in many disease processes, including cancer and inherited disorders of the neuromuscular systems. However, the cellular circuits that control splicing regulation are mostly unknown. New methods that measure splicing changes on a genome-wide scale make possible the discovery of coordinately regulated networks of alternative splicing. The elucidation of the regulatory events underlying this coordinate control will be essential for understanding how groups of exons are controlled during development and disease. This project will support the continued development and dispersal of parallel technologies for measuring alternative splicing initiated by the Black, Fu and Ares labs through prior R24 funding. In the initial project period, several different approaches were developed. Most notably, two splicing- sensitive microarrays, one for mouse and one for human cells, each measuring splicing of about 1300 alternative splicing events in about 1000 genes, were successfully designed, printed and used to capture and analyze data. These arrays were applied to a diverse set of experiments and were successful in uncovering several systems of coordinate splicing control important in cellular differentiation and homeostasis. We propose to continue this productive collaboration with the following aims: (1) We will continue to apply the arrays and analysis methods produced during the previous funding period to questions of splicing regulation, and we will expand their use to additional laboratories studying splicing; (2) we will improve the design and analysis of splicing-sensitive arrays to make them more comprehensive, and reliable, as well as more widely available; and (3) we will develop a promising new approach to genome-wide splicing analysis using high density sequencing methods. This project will broaden the study of splicing regulation to the level of the whole genome, allowing the integration of specific splicing regulatory pathways into our understanding of gene regulation and genome function. PUBLIC HEALTH RELEVANCE Many human diseases, including both cancer and inherited diseases of the neuromuscular systems, are caused by alterations in gene function through a process called alternative pre-mRNA splicing. Although individual changes in splicing have been linked to particular disorders, it is not well understood how programs of splicing affect the larger biology of the cell, and hence how abnormalities in these programs lead to disease. This project will extend our work on methods for examining splicing regulation on a genome wide scale that will allow elucidation of these larger programs of genetic change in disease.

描述（由申请人提供）：选择性剪接是控制哺乳动物基因表达的关键过程，也是蛋白质多样性的主要来源。剪接调节错误与许多疾病过程有关，包括癌症和神经肌肉系统的遗传性疾病。然而，控制剪接调节的细胞电路大多是未知的。在全基因组范围内测量剪接变化的新方法使得发现选择性剪接的协调调控网络成为可能。阐明这种协调控制背后的调控事件对于理解在发育和疾病过程中如何控制外显子组至关重要。该项目将支持 Black、Fu 和 Ares 实验室通过先前的 R24 资助发起的测量选择性剪接的并行技术的持续开发和推广。在项目初期，开发了几种不同的方法。最值得注意的是，两种剪接敏感微阵列（一种用于小鼠，一种用于人类细胞）被成功设计、打印并用于捕获和分析数据，每种微阵列测量约1000个基因中约1300个可变剪接事件的剪接。这些阵列被应用于一系列不同的实验，并成功地揭示了在细胞分化和稳态中重要的几个协调剪接控制系统。我们建议继续这种富有成效的合作，以实现以下目标：（1）我们将继续将上一个资助期间产生的阵列和分析方法应用于剪接调控问题，并将其用途扩大到更多研究剪接的实验室；（2）改进拼接敏感阵列的设计和分析，使之更加全面、可靠、应用更加广泛； (3)我们将开发一种有前途的新方法，使用高密度测序方法进行全基因组剪接分析。该项目将把剪接调控的研究拓展到全基因组水平，从而将特定剪接调控途径整合到我们对基因调控和基因组功能的理解中。公共卫生相关性许多人类疾病，包括癌症和神经肌肉系统的遗传性疾病，都是由基因功能通过称为选择性前 mRNA 剪接的过程发生改变引起的。尽管剪接的个体变化与特定疾病有关，但人们尚不清楚剪接程序如何影响细胞的更大生物学，以及这些程序的异常如何导致疾病。该项目将扩展我们在全基因组范围内检查剪接调控方法的工作，这将有助于阐明疾病中这些更大的遗传变化程序。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD).

在面肩肱型肌营养不良症 (FSHD) 小鼠模型中，FRG1 下调 Rbfox1 并改变钙蛋白酶 3 剪接。

DOI：
发表时间：
2013
期刊：
影响因子：
4.5
作者：
Pistoni, Mariaelena;Shiue, Lily;Cline, Melissa S;Bortolanza, Sergia;Neguembor, Maria Victoria;Xynos, Alexandros;Ares Jr, Manuel;Gabellini, Davide
通讯作者：
Gabellini, Davide