Structure-Function Relationship of Glycosaminoglycans

糖胺聚糖的结构-功能关系

• 批准号: 8911962
• 负责人: RAM SASISEKHARAN
• 金额: $ 5万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911962
• 关键词: Address; Adult Respiratory Distress Syndrome; Aerosols; Affect; Affinity; Air; American; Americas; Amino Acids; Animal Model; Apical; Applications Grants; Avian Influenza; Avian Influenza A Virus; Back; Base Pairing; Benchmarking; Bibliography; Binding; Binding Proteins; Binding Sites; Biochemical; Bioinformatics; Biological; Biological Models; Biotechnology; Birds; British Columbia; Cells; Cessation of life; Characteristics; China; Communicable Diseases; Complex; Conjunctivitis; Coupled; Databases; Detection; Development; Disease; Disease Outbreaks; Economic Burden; Emerging Communicable Diseases; Enzymes; Epidemiology; Epithelial Cells; Epithelium; European; Evaluation; Evolution; Family suidae; Ferrets; Fibroblast Growth Factor; Flu virus; Foundations; Funding; Genes; Genetic; Gland; Glycosaminoglycans; Goblet Cells; Grant; H5 hemagglutinin; H7N7; Health; Hemagglutinin; Hematoxylin and Eosin Staining Method; Heparin; Human; Human Characteristics; Human Pathology; Immune response; Immunization; In Vitro; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H2N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N9 Subtype; Influenza A virus; Influenza Hemagglutinin; Informatics; Investigation; Journals; Lead; Lectin; Link; Mass Spectrum Analysis; Medicine; Membrane Fusion; Microarray Analysis; Modeling; Molecular; Molecular Conformation; Mucins; Mus; Nature; New England; Pathogenesis; Pathology; Phase I Clinical Trials; Physiological; Polymerase; Polysaccharides; Population; Property; Protein Structure Databases; Proteins; Public Health; Publications; Publishing; Relative (related person); Reporting; Respiratory System; Respiratory tract structure; Risk; Scheme; Science; Specificity; Staining method; Stains; Structural Protein; Structure; Structure of respiratory epithelium; Structure-Activity Relationship; Sulfatases; Surface; Surveys; System; Technology; Testing; Text; Time; Tissues; Trachea; United States; United States National Academy of Sciences; Vaccines; Viral; Virus; Virus Diseases; Wood material; Work; Yang; abstracting; airway epithelium; base; cell type; cost; experience; gain of function; gustin; human tissue; immunogenicity; influenza virus strain; influenzavirus; insight; mutant; novel; pandemic disease; pandemic influenza; preference; protein structure; receptor; receptor binding; respiratory; sialic acid receptor; swine flu; tissue tropism; tool; tool development; transmission process

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Given the various tools that were developed to study Glycosaminoglycan (GAG) mixtures (specific aims 1), studying glycan mixtures in the context of glycans present in the upper airways became an obvious extension of this work. The glycan mixtures - especially the sialylated glycans present in the epithelial cells- provided the important reference point to these being critical receptors for Influenza A viruses. We had furthermore established a foundation to study the protein-GAG interactions, using various GAG degrading enzymes over the years. Based on the fact that many of these enzymes, and other GAG or glycan binding proteins, have poor sequence identity [this includes key sulfatases, fibroblast growth factors or influenza virus hemagglutinin (HA)], we developed newer tools to study GAG-protein interactions, which were broadly applicable to protein-glycan interactions. Newer analytical and structural tools were developed under specific aims 1 and as part of specific aims 2. We developed not only GAG/glycan databases, but also protein structural databases to study the diversity of glycan- protein interactions. Integration of these two approaches-glycan conformation coupled with protein structure and database-enabled us to tackle a fundamental question related to glycan specificity of influenza A viruses, which turned out to be the ideal model system to validate our approach. Given extensive glycan diversity and the mixture of glycans present in the apical epithelium, for the first time we demonstrated that glycan topology is a key determinant for human adaptation of influenza viruses (published in Nature Biotechnology). Our prediction that the then emerging 2009 H1N1 "swine flu" virus was not efficient in transmission (published in Science 2009) was further validated and observed due to poor transmission of this virus in humans (published in NEJM 2009). More recently, with the outbreak of the 2013 H7N9, we rapidly investigated the receptor specificity of the H7N9 HA and published our observations (along with our predictions on H5N1) back-to-back in the journal Cell. The R37 grant application will address key questions related to glycan topology and HA binding using complementary analytical and structural approaches.

在此处输入文本，这是您应用程序的新摘要信息。本节必须不 超过30行文本。 鉴于开发了用于研究糖胺聚糖（GAG）混合物的各种工具 （特定目的1），在上呼吸道中存在的聚糖中研究聚糖混合物 成为这项工作的明显扩展。聚糖混合物 - 尤其 上皮细胞中存在的聚糖 - 提供了这些存在的重要参考点 流感病毒的关键受体。我们还建立了研究的基础 多年来，使用各种插入酶的蛋白质相互作用。基于 这些酶，其他插科打结合蛋白的许多事实都很差 序列身份[这包括关键硫酸酶，成纤维细胞生长因子或流感病毒 血凝素（HA）]，我们开发了新的工具来研究Gag蛋白质相互作用，这是 广泛适用于蛋白质 - 聚糖相互作用。较新的分析和结构工具是 根据特定目的1和特定目的的一部分开发2。我们不仅开发了 GAG/GLYCAN数据库，以及蛋白质结构数据库，以研究聚糖的多样性 蛋白质相互作用。这两种方法的整合 - 聚糖构象与 蛋白质结构和数据库启用我们解决与聚糖有关的基本问题 流感病毒的特异性，事实证明是验证我们的理想模型系统 方法。给定广泛的聚糖多样性和顶端存在的聚糖的混合物 上皮，我们首次证明了聚糖拓扑是人类的关键决定因素 流感病毒的适应（自然生物技术发表）。我们的预测当时 新兴的2009 H1N1“猪流感”病毒在传播方面不高（发表在科学上 2009年）进一步验证并观察到由于该病毒在人类中的传播不良而被观察到 （发表在NEJM 2009中）。最近，随着2013 H7N9的爆发，我们迅速 研究了H7N9 HA的受体特异性并发表了我们的观察结果（以及 我们对H5N1的预测）在杂志的单元格中背对背。 R37赠款申请将解决 使用补充分析和 结构方法。