Software for automated interpretation of heparan sulfate tandem mass spectra

用于自动解释硫酸乙酰肝素串联质谱的软件

基本信息

批准号：
8984998
负责人：
JOSEPH ZAIA
金额：
$ 32.97万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8984998
关键词：
Abbreviations Adopted Adoption Adult Algorithms Anabolism Binding Biochemistry Bioinformatics Biological Cell surface Chromatography Communities Complex Complex Mixtures Computer software Cytoplasmic Granules Data Data Analyses Development Disease Dissociation Electron Transport Electrons Embryonic Development Endoplasmic Reticulum Enzymes Event Extracellular Matrix Family GAG Gene Glycosaminoglycans Golgi Apparatus Growth Factor Growth Factor Receptors Health Heparitin Sulfate Heterogeneity Human Imagery Inorganic Sulfates Isomerism Laboratories Licensing Liquid Chromatography Mass Spectrum Analysis Methods Modification Mutant Strains Mice Nature Output Pathway interactions Performance Pharmaceutical Preparations Phenotype Physiological Physiology Polysaccharides Process Protein Binding Protein Isoforms Proteomics Publishing Resolution Running Scientist Series Source Code Specificity Stimulus Structure System Tissues Unspecified or Sulfate Ion Sulfates biomedical scientist cell type chemical property computerized data processing design drug development instrument liquid chromatography mass spectrometry mass spectrometer meetings proteoglycan core protein receptor response sulfation sulfotransferase web services

项目摘要

DESCRIPTION (provided by applicant): Software for automated interpretation of heparan sulfate tandem mass spectra the expression of heparan sulfate (HS) is required for embryonic development and the functioning of every physiological system. Present in intracellular granules, on cell surfaces and in extracellular matrices, HS binds to growth factor families and their receptors. These binding interactions serve to modulate cellular responses to growth factor stimuli in a cell-type and developmental state specific manner. The challenge to exploitation of HS structures as drugs lies in the nature of their biosynthesis and in their chemical properties. HS chains are assembled in the endoplasmic reticulum and Golgi apparatus by a series of enzymes acting in a non-template driven manner. Chains are first polymerized and then subject to modification events that produce mature chains with a regulated domain structure overlaid by substantial heterogeneity. As the HS chain biosynthesis proceeds, the number of biosynthetic enzymatic isoforms increases. These enzymes, including 6O- sulfotransferases and 3O-sulfotransferases, are expressed in a tissue and cell-type specific manner and are believed to modify substrates with isoform specificity. The result is HS chains that have phenotype-specific structure and protein binding functions. Despite the availability of mouse mutants for many of the biosynthetic enzymes, progress in HS biomedicine has suffered from the lack of widely adopted sequencing methods. Over the past few years, however, electron activated dissociation methods (ExD) have been developed in mass spectrometry laboratories. These methods, including electron detachment dissociation (EDD) and negative electron detachment dissociation (NETD) demonstrate feasibility of instrumental sequencing of HS saccharides. The advantage to these methods is that they require no or minimal derivatization, are compatible with high throughput, and provide rich structural information of the HS saccharides. The tandem mass spectra are highly complex, however, and tailor-made bioinformatics methods are necessary to convert raw data into sequences. We have demonstrated feasibility of an algorithm (HS-SEQ) for sequencing HS saccharide from ExD tandem mass spectra. We now propose to develop HS-SEQ so that it can provide better performance and full features supporting automated HS analysis, and be easily used by the wider biomedical community. The availability of mass spectrometers with NETD or EDD capability will grow rapidly over the next few years. We will develop a pipeline for data processing that includes all steps necessary to go from raw data to sequence information. This pipeline will be designed for use by biomedical scientists familiar with HS biochemistry and/or proteomics methods. The HS- SEQ pipeline will run as a web service and be available in source code and binary installer form under a Creative Commons license

描述（由申请人提供）：用于自动解释硫酸乙酰肝素串联质谱的软件硫酸乙酰肝素（HS）的表达是胚胎发育和每个生理系统功能所必需的，存在于细胞内颗粒、细胞表面和细胞外基质中。，HS 与生长因子家族及其受体结合，以细胞类型和发育状态特异性方式调节细胞对生长因子刺激的反应。 HS 结构作为药物取决于其生物合成的性质和化学性质，HS 链在内质网和高尔基体中通过一系列以非模板驱动方式作用的酶进行组装，然后进行聚合。产生具有显着异质性的受调节结构域结构的成熟链的修饰事件随着 HS 链生物合成的进行，生物合成酶异构体的数量增加。包括 6O- 磺基转移酶和 3O- 磺基转移酶在内的酶以组织和细胞类型特异性的方式表达，并且被认为可以修饰具有同种型特异性的底物，从而产生具有表型特异性结构和蛋白质结合功能的 HS 链。然而，随着许多生物合成酶的小鼠突变体的出现，HS生物医学的进展因缺乏广泛采用的测序方法而受到影响。质谱实验室已开发出活化解离方法 (ExD)，这些方法包括电子脱离解离 (EDD) 和负电子脱离解离 (NETD)，证明了 HS 糖类仪器测序的可行性。没有或最少的衍生化，与高通量兼容，并提供丰富的 HS 糖的结构信息，然而，串联质谱是高度复杂的，并且是定制的。生物信息学方法对于将原始数据转换为序列是必要的。我们已经证明了从 ExD 串联质谱中测序 HS 糖的算法（HS-SEQ）的可行性。我们现在建议开发 HS-SEQ，以便它能够提供更好的性能和完整的结果。支持自动化 HS 分析，并易于被更广泛的生物医学界使用具有 NETD 或 EDD 功能的质谱仪的可用性将在未来几年内快速增长，我们将开发一个包括所有数据处理的管道。从原始数据到序列信息所需的步骤。该管道将设计供熟悉 HS 生物化学和/或蛋白质组学方法的生物医学科学家使用。HS-SEQ 管道将作为网络服务运行，并以源代码和二进制形式提供。知识共享许可下的安装程序形式