Systems Biology of Glycosylation

糖基化的系统生物学

• 批准号: 10374428
• 负责人: SRIRAM NEELAMEGHAM
• 金额: $ 54.98万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-05 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374428
• 关键词: Abbreviations; Address; Adhesions; Anabolism; Animals; Atlases; Bar Codes; Basic Science; Binding; Biochemical Pathway; Biochemical Process; Bioinformatics; Biological Assay; Biological Markers; Biological Process; Blood; Blood Cells; CD34 gene; CRISPR library; CRISPR screen; Cell Adhesion; Cell Adhesion Molecules; Cell Adhesion Process; Cell Line; Cell physiology; Cells; Cellular Metabolic Process; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Complex; Computational Biology; Computers; Coupling; Data; Development; Disease; Ear; Early Diagnosis; Endothelial Cells; Enzymes; Epigenetic Process; Event; Family; Flow Cytometry; Fucose; Funding; Galactose; Gene Expression Alteration; Gene Expression Profile; Gene Targeting; Genes; Genetic; Glycoconjugates; Grant; HL60; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Human; Immunity; Individual; Inflammation; Inflammatory; Knock-out; Knowledge; Lead; Lectin; Leukocytes; Libraries; Link; Mammalian Cell; Maps; Mass Spectrum Analysis; Measurement; Measures; Mechanics; Mediating; Methods; Microfluidics; Modeling; Molecular; Mononuclear; Mus; Myelogenous; Myeloid Cells; National Heart, Lung, and Blood Institute; Natural Immunity; Nature; Neoplasm Metastasis; Nomenclature; Organism; Pathway interactions; Pattern; Polysaccharides; Post-Translational Protein Processing; Proteins; Role; S-nitro-N-acetylpenicillamine; Selectins; Series; Sialic Acids; Signal Transduction; Specificity; Structure; System; Systems Biology; Technology; Testing; Transcript; Translating; Transplantation; Vascular Endothelial Cell; Work; base; carbohydrate binding protein; clinical diagnostics; computer framework; cost; disease diagnostic; experimental study; genome-wide; glycoproteomics; glycosylation; glycosyltransferase; granulocyte; in vivo; inhibitor; macrophage; model building; molecular scale; monocyte; network models; neutrophil; next generation sequencing; novel; outcome prediction; patient stratification; peripheral blood; precision medicine; programs; relational database; sequencing platform; sialyl Lewis x; single cell analysis; single-cell RNA sequencing; small molecule; small molecule inhibitor; sugar; tool; transcription factor; transcriptome; transcriptomics; user-friendly; web site

This is the renewal application of a grant that has been supported as part of the NHLBI Systems Biology program. It deals with the subject of glycosylation, a ubiquitous and complex post-translational modification in mammalian cells. Glycans decorate a vast majority of mammalian proteins. They absolutely control or fine-tune a number of cellular processes in higher organisms including development, immunity, inflammation, bleeding and metastasis. Glycan structures change due to alterations in cell metabolism, development and signaling events that perturb the underlying transcriptome. A systematic understanding of the factors (genetic and epigenetic) controlling glycosylation is currently unavailable. This is however important for two reasons: i. Such knowledge can help establish quantitative links between different cell systems, so that knowledge gained in the study of one system can be applied to predict the outcome in another. ii. Gene transcript measurements are now being used in clinical diagnostics, and the advent of next generation sequencing (NGS) has dramatically reduced the cost of such assays. If a relation between changes in the pattern of gene expression and alterations in glycan structures is established, disease-associated glycan biomarkers may be assayed using standard gene sequencing methods. This can enable both early diagnosis and patient stratification during precision medicine applications. Based on the above, the current proposal addresses the hypothesis that “Coupling systems based quantitative, analytical experimentation with model building can help relate cellular glycomics changes to the underlying transcriptome”. This proposition will be tested by performing a series of studies using blood leukocytes involved in innate immunity and by relating findings to inflammatory leukocyte-endothelial cell adhesion mechanics. The specific aims are: 1. To develop a blood glycan atlas using single-cell analysis on NGS platform and glycoProbe based mass spectrometry. This aim will result in a relational database that describes the glycoEnzymes regulating the biosynthesis of specific glycan structures in three myeloid/monocytic blood cell lines, primary human blood and in CD34+ hematopoietic stem/progenitor cells (HSPC). 2: To develop a complementary experiment-modeling framework to relate glycogene expression to glycan structure. This aim extends concepts in Aim 1, only focusing on blood cells that are being differentiated down neutrophil or macrophage lineages. Emerging data will yield glycogene regulatory network maps that identify novel controllers of cellular glycosylation profile. 3: To test the roles of selected small molecules, transcription factors (TFs) & glycogene checkpoints during leukocyte-endothelial cell adhesion ex vivo and in vivo. Here, we determine the ability of data-driven computer predictions and molecular studies, to identify new checkpoints regulating human inflammatory leukocyte adhesion. Overall, the study scales from the molecular, to cell and whole animal levels. It will result in state-of-the-art systems biology computational and experimental tools to enhance our understanding of cellular glycosylation, blood glycans, and its impact on human inflammatory diseases.

这是作为NHLBI Systems Biology计划的一部分支持的赠款的续签应用。 它涉及糖基化的主题，这是一种无处不在且复杂的哺乳动物的翻译后修饰 细胞。 Glycans装饰了绝大多数哺乳动物蛋白。他们绝对控制或微调许多 较高生物体的细胞过程，包括发育，免疫学，注射，出血和转移。 由于细胞代谢，发育和信号事件的改变，聚糖结构发生了变化 基础转录组。对控制因素（遗传和表观遗传）的系统理解 糖基化目前不可用。但是，这很重要，原因有两个：i。这样的知识可以帮助 在不同的细胞系统之间建立定量联系，以便在一个系统的研究中获得的知识 可以应用于另一个结果中的结果。 ii。基因转录物测量现在正在临床中使用 诊断和下一代测序的冒险（NGS）大大降低了这种成本 测定。如果基因表达模式的变化与聚糖结构的变化之间的关系是 可以使用标准基因测序方法测定建立的，与疾病相关的聚糖生物标志物。 这可以使早期诊断和精确医学应用期间的患者分层同时分层。基于 以上，当前的提案解决了以下假设：“基于耦合系统的定量， 使用模型构建的分析实验可以帮助将细胞糖胶质变化与 基础转录组”。该命题将通过使用血液进行一系列研究来测试 白细胞与先天免疫有关，并通过将发现与炎症性白细胞 - 内皮细胞联系起来 粘附力学。具体目的是：1。使用单细胞分析开发血聚糖地图集 NGS平台和基于糖探针的质谱法。这个目标将导致一个关系数据库 描述了三个髓样/单核细胞中特定聚糖结构的生物合成的糖酶 血细胞系，原代人血和CD34+造血干/祖细胞（HSPC）。 2：发展 一个完整的实验模型框架，将糖基化表达与聚糖结构相关联。这个目标 在AIM 1中扩展概念，仅关注正在降低中性粒细胞或 巨噬细胞谱系。新兴数据将产生糖基因调节网络图，以识别新型控制器 细胞糖基化谱。 3：测试选定的小分子的作用，转录因子（TFS）＆ 白细胞 - 内皮细胞粘合剂的体内和体内的糖基因检查点。在这里，我们确定 数据驱动的计算机预测和分子研究的能力，确定调节人类的新检查点 炎症白细胞粘附。总体而言，研究从分子到细胞和整个动物水平。 这将导致最先进的系统生物学计算和实验工具，以增强我们的 了解细胞糖基化，血糖及其对人类炎症性疾病的影响。