SELECTIN MEDIATED CELL ADHESION UNDER HYDRODYNAMIC SHEAR

选择流体力学剪切下介导的细胞粘附

基本信息

项目摘要

This research project examines the function of carbohydrate chains that are O-linked to leukocyte cell- surface glycoproteins. By acting as the natural ligands of the selectin family of adhesion molecules, these glycoproteins control the rates of leukocyte adhesion in the human vasculature during normal immune response, inflammatory diseases and certain types of cardiovascular disorders. It is widely believed that controlling the rate of leukocyte adhesion in vascular disorders can lead to new therapies to combat these ailments. Thus, in the current proposal, we evaluate two mechanisms for controlling selectin-ligand binding. In Aim 1, we develop and test the ability of unique molecules based on an unusual disaccharide carbohydrate structure (GalNAc(31,3GalNAca-O-Methyl) to competitively inhibit selectin binding interactions with its ligand. Our preliminary data suggests that this disaccharide alone can bind P- selectin. We also demonstrate that appropriate modification of this unit can dramatically enhance the binding affinity of the resulting carbohydrate for selectins, when compared with the prototypic selectin ligand sialyl Lewis-X. In Aim 2, we test an approach where small-molecule metabolic inhibitors are designed based on the structure of monosaccharides that compose natural selectin ligands. These modified monosaccharidesare fed to cells in order to interfere with the biosynthesis of specific carbohydrate epitopes on the glycoprotein ligands of selectins. More specifically, these molecules are directed to alter either the core or terminal residues of glycans expressed by an important leukocyte selectin-ligand called PSGL-1 (P-selectin glycoprotein ligand- 1). We evaluate the ability and mechanism by which these chemical inhibitors permeate cells, engage and modify glycan biosynthetic pathways and inhibit cell adhesion. In Aim 3, to complement the experimental work above, a Systems Biology based mathematical model is developed to simulate biochemical networks that regulate O-glycan biosynthesis in leukocytes. Many of the assumptions in this mathematical model are experimentally validated. Diverse experimental methods are applied to accomplish the above three aims. These include cell adhesion studies under controlled flow, in vivo experiments in a mouse model of acute inflammation, western blot analysis, molecular biology based approaches, flow cytometry, surface plasmon resonance and liquid chromatography. In the long run, we anticipate that small-molecule selectin-antagonists will be identified from this work that may aid future drug design. Mathematical models developed will enhance the application of metabolic engineering principles in the area of biological chemistry. Such analysis can also provide the rationale for the chemical synthesis of new inhibitors and for interpretation of experimental observations.
这项研究项目研究了O-连接到白细胞的碳水化合物链的功能。 表面糖蛋白。通过作为黏附分子的选择素家族的天然配体,这些 糖蛋白控制正常免疫状态下人体血管中白细胞的粘附率 反应、炎症性疾病和某些类型的心血管疾病。人们普遍认为 控制血管疾病中的白细胞粘附率可以导致对抗这些疾病的新疗法 病痛。因此,在目前的提案中,我们评估了两种控制选择素-配体结合的机制。 在目标1中,我们开发并测试了基于一种不寻常的二糖的独特分子的能力。 糖类结构(GalNAc(31,3GalNAca-O-Methyl))竞争性抑制选择素结合作用 以及它的配体。我们的初步数据表明,仅此二糖就能与P-选择素结合。我们也 证明对该单位进行适当的修饰可以显著增强 与典型的选择素配体sialyl Lewis-X比较时,得到的选择素的碳水化合物。在AIM 2,我们测试了一种基于结构设计小分子代谢抑制剂的方法 组成天然选择素配体的单糖。这些修饰的单糖被喂给细胞 为了干扰糖蛋白配体上特定碳水化合物表位的生物合成 选择素。更具体地说,这些分子被指示改变其核心或末端残基。 糖链由一种重要的白细胞选择素配体PSGL-1(P-选择素糖蛋白配体-1)表达。 1)。我们评估了这些化学抑制物渗透细胞、参与和 修饰多糖生物合成途径,抑制细胞黏附。在目标3中,作为实验的补充 在此基础上,建立了一个基于系统生物学的数学模型来模拟生化网络 来调节白细胞中O-糖链的生物合成。该数学模型中的许多假设是 经过实验验证。为了达到上述三个目的,我们采用了多种实验方法。 这些研究包括受控流动下的细胞黏附研究,急性胰腺炎小鼠模型的体内实验。 炎症,蛋白质印迹分析,基于分子生物学的方法,流式细胞术,表面等离子 共振层析法和高效液相色谱法。从长远来看,我们预计小分子选择素拮抗剂 将从这项工作中确定可能有助于未来的药物设计。开发的数学模型将 加强代谢工程原理在生物化学领域的应用。这样的分析 也可以为化学合成新的缓蚀剂和解释 实验观察。

项目成果

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SRIRAM NEELAMEGHAM其他文献

SRIRAM NEELAMEGHAM的其他文献

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{{ truncateString('SRIRAM NEELAMEGHAM', 18)}}的其他基金

Application of machine/deep-learning to the systems biology of glycosylation
机器/深度学习在糖基化系统生物学中的应用
  • 批准号:
    10594074
  • 财政年份:
    2022
  • 资助金额:
    $ 22.21万
  • 项目类别:
Engineering of glycosyltransferases to obtain glycan binding proteins
糖基转移酶工程以获得聚糖结合蛋白
  • 批准号:
    10259786
  • 财政年份:
    2020
  • 资助金额:
    $ 22.21万
  • 项目类别:
High content glycomics analysis using next generation sequencing technology
使用下一代测序技术进行高内涵糖组学分析
  • 批准号:
    9924616
  • 财政年份:
    2019
  • 资助金额:
    $ 22.21万
  • 项目类别:
High content glycomics analysis using next generation sequencing technology
使用下一代测序技术进行高内涵糖组学分析
  • 批准号:
    9765667
  • 财政年份:
    2019
  • 资助金额:
    $ 22.21万
  • 项目类别:
Systems Biology of Glycosylation
糖基化的系统生物学
  • 批准号:
    8327859
  • 财政年份:
    2011
  • 资助金额:
    $ 22.21万
  • 项目类别:
Systems Biology of Glycosylation
糖基化的系统生物学
  • 批准号:
    10558673
  • 财政年份:
    2011
  • 资助金额:
    $ 22.21万
  • 项目类别:
Systems Biology of Glycosylation
糖基化的系统生物学
  • 批准号:
    8145434
  • 财政年份:
    2011
  • 资助金额:
    $ 22.21万
  • 项目类别:
Systems Biology of Glycosylation
糖基化的系统生物学
  • 批准号:
    8885874
  • 财政年份:
    2011
  • 资助金额:
    $ 22.21万
  • 项目类别:
Systems Biology of Glycosylation
糖基化的系统生物学
  • 批准号:
    8521357
  • 财政年份:
    2011
  • 资助金额:
    $ 22.21万
  • 项目类别:
Systems Biology of Glycosylation
糖基化的系统生物学
  • 批准号:
    10374428
  • 财政年份:
    2011
  • 资助金额:
    $ 22.21万
  • 项目类别:

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