HEPARANOMICS: STRUCTURE-FUNCTION RELATIONSHIPS

肝脏组学：结构与功能的关系

基本信息

批准号：
7884258
负责人：
KUBERAN BALAGURUNATHAN
金额：
$ 28.31万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-26 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7884258
关键词：
Adult Animal Model Antithrombins Binding Sites Biological Biological Assay Biological Process Brain Cell surface Chemicals Cleaved cell Code Complex Coupled Development Disease Drosophila genus Enzymes Escherichia coli Extracellular Matrix FGF1 gene FGF2 gene Fibroblast Growth Factor Fibroblast Growth Factor 1 Fibroblast Growth Factor 8 Fibroblast Growth Factor Receptors Foundations Glycobiology Growth Factor Growth Factor Receptors Heart Heparin Binding Heparitin Sulfate High Pressure Liquid Chromatography Human Development Imagery Indium Individual Inorganic Sulfates Knowledge Length Libraries Ligands Light Location Lung Methodology Modification Molecular Oligosaccharides Pathologic Processes Pathway interactions Pattern Physiological Physiological Processes Platelet-Derived Growth Factor Play Polysaccharides Protein Isoforms Proteins Proteoglycan Radiolabeled Reagent Recombinants Research Research Personnel Role Screening procedure Signal Transduction Signaling Molecule Structure Structure-Activity Relationship Substrate Specificity Sulfur System Techniques Testing Time Unspecified or Sulfate Ion Sulfates Validation Vascular Endothelial Growth Factors Zebrafish base biological systems design epimerase functional group gel mobility shift assay heparitinase liquid chromatography mass spectrometry lung development member morphogens novel programs radiotracer receptor research study response stable isotope structural biology sugar sulfation sulfotransferase

项目摘要

DESCRIPTION (provided by applicant): Heparan sulfates (HS) are abundantly expressed on the cell surface and in the extracellular matrix as proteoglycans with differential sulfation pattern, chain length and number of chains leading to vast structural features. Each chain interacts simultaneously with numerous proteins including a variety of signaling molecules, morphogens, receptors, etc and orchestrates various biological functions. Modulation of their biosynthetic pathways has begun to shed light on their role in such model organisms as zebra fish, c. elegans, drosophila, etc. However, the lack of efficient synthetic approaches coupled with a small amount of HS chains isolated from animal models has limited our knowledge of how these molecules regulate various physiological and pathological processes at the molecular level. The central hypothesis of this proposal is that multiple oligosaccharide sequences with conserved critical groups may elucidate the same biological response or that a given oligosaccharide sequence with a set of critical groups may elucidate more than one biological response. Determining those critical groups and their spatial distance would be sufficient to determine the rules that dictate HS-protein interactions. Development of a general enzymatic approach for the rapid assembly of HS of various sizes should allow us to test our hypothesis and to delineate the rules that dictate HS-protein interactions. We propose to construct the oligosaccharide libraries and screen their ability to form signaling complex with various growth factors and receptors that play a central role in heart, lung and brain development. With the aid of stable isotopes, we will then develop novel structural biology approaches to elucidate the critical groups that attribute a biological function. The knowledge gained in synthesizing ATIII binding sites will be used in designing diverse size-based HS libraries that should be the key to defining all interacting proteins and elucidating the chemical rules by which such interactions take place. This proposed study should establish a firm foundation for the glycobiology of proteoglycans.

描述（由申请人提供）：硫酸乙酰肝素（HS）作为蛋白聚糖在细胞表面和细胞外基质中大量表达，具有不同的硫酸化模式、链长和链数，从而产生巨大的结构特征。每条链同时与多种蛋白质相互作用，包括各种信号分子、形态发生素、受体等，并协调各种生物功能。对它们生物合成途径的调节已经开始揭示它们在斑马鱼、c.然而，由于缺乏有效的合成方法以及从动物模型中分离出的少量HS链，限制了我们对这些分子如何在分子水平上调节各种生理和病理过程的了解。该提议的中心假设是具有保守关键基团的多个寡糖序列可以阐明相同的生物反应，或者具有一组关键基团的给定寡糖序列可以阐明多个生物反应。确定这些关键基团及其空间距离足以确定决定 HS-蛋白质相互作用的规则。开发用于快速组装各种大小的 HS 的通用酶方法应该使我们能够检验我们的假设并描绘决定 HS-蛋白质相互作用的规则。我们建议构建寡糖文库并筛选其与各种生长因子和受体形成信号复合物的能力，这些生长因子和受体在心脏、肺和大脑发育中发挥核心作用。在稳定同位素的帮助下，我们将开发新的结构生物学方法来阐明赋予生物学功能的关键基团。在合成 ATIII 结合位点中获得的知识将用于设计不同的基于大小的 HS 文库，这应该是定义所有相互作用蛋白质和阐明发生此类相互作用的化学规则的关键。这项拟议的研究应该为蛋白多糖的糖生物学奠定坚实的基础。