NOVEL CARBOXYLATED GLYCANS IN CELL ADHESION

细胞粘附中的新型羧化聚糖

基本信息

批准号：
7723694
负责人：
Hudson H. Freeze
金额：
$ 0.81万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7723694
关键词：
Adhesions Advanced Glycosylation End Products Annexin A1 Binding Carbohydrates Cell Adhesion Cell Surface Receptors Cell physiology Computer Retrieval of Information on Scientific Projects Database Dimensions Endothelial Cells Endothelium Esters Event Funding Grant HMGB1 Protein In Vitro Inflammation Inorganic Sulfates Institution Lectin Leukocytes Ligand Binding Ligands Link Mediating Modification Monoclonal Antibodies Mus Neoplasm Metastasis Neurites Peritoneal Polysaccharides Process Proteins Research Research Personnel Resources Role S100A12 gene Selectins Septic Shock Sialic Acids Signal Transduction Signal Transduction Pathway Source Structure United States National Institutes of Health Unspecified or Sulfate Ion Sulfates Uronic Acids base cancer cell carboxylate glycosylation human S100A12 protein in vivo inorganic phosphate intraperitoneal novel novel therapeutics receptor receptor for advanced glycation endproducts receptor function tumor tumor growth

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. One of the key cellular processes involved in tumor growth, invasion, and metastasis is the binding of an HMGB1 protein, amphoterin, to the cell surface receptor for advanced glycation end products (RAGE), with subsequent activation of signal transduction pathways. We found that this binding involves novel glycans expressed on RAGE. This proposal explores the structure of the novel glycans and the role of the glycans in RAGE-amphoterin mediated signaling events, including tumor growth and metastasis. Mammalian lectins often bind to anionic glycans containing sialic acid, phosphate, sulfate esters, or uronic acids. We found new carboxylate modifications on endothelial cell N-linked glycans that are completely distinct from selectin ligands. These novel glycans mediate endothelium/leukocyte interaction, intraperitoneal inflammation, and neurite outgrowth. A specific monoclonal antibody against the glycans blocks peritoneal inflammation in the mouse. The carboxylated glycans bind to four proteins: amphoterin, annexin-I, S100A8/A9 and S100A12, which have been variably linked to neurite outgrowth, tumor growth and metastasis, inflammation and septic shock. We also found evidence that these novel glycans are present on RAGE, a well-documented signal-transducing receptor for amphoterin. Based on our findings, we hypothesize that the novel glycans may have an in vivo role in tumor growth and metastasis, and that glycosylation of RAGE could be important in tumor related processes. We therefore propose to: 1. Establish the structure of the novel carboxylated glycans on RAGE. 2. Determine the significance of carboxylated glycans in defining the pathophysiological functions of RAGE, in terms of ligand binding and intracellular signaling. 3. Assess the role of carboxylated glycans in mediating amphoterin-RAGE interactions in vitro and in vivo leading to tumor growth, invasion, and metastasis. The fundamental understanding of the structure of these novel glycans together with their effects on tumor growth and metastasis are likely to add an important dimension to carbohydrate based adhesion in normal and malignant cells. A novel therapeutic approach may also emerge.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目和研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。肿瘤生长、侵袭和转移中涉及的关键细胞过程之一是 HMGB1 蛋白（两性蛋白）与细胞表面晚期糖基化终末产物 (RAGE) 受体的结合，随后激活信号转导途径。我们发现这种结合涉及 RAGE 上表达的新聚糖。该提案探讨了新型聚糖的结构以及聚糖在 RAGE-两性蛋白介导的信号事件（包括肿瘤生长和转移）中的作用。哺乳动物凝集素通常与含有唾液酸、磷酸盐、硫酸酯或糖醛酸的阴离子聚糖结合。我们在内皮细胞 N 连接聚糖上发现了新的羧酸盐修饰，这些修饰与选择素配体完全不同。这些新型聚糖介导内皮/白细胞相互作用、腹膜内炎症和神经突生长。针对聚糖的特异性单克隆抗体可阻断小鼠的腹膜炎症。羧化聚糖与四种蛋白质结合：两性蛋白、膜联蛋白-I、S100A8/A9 和 S100A12，这些蛋白质与神经突生长、肿瘤生长和转移、炎症和感染性休克存在不同的相关性。我们还发现证据表明这些新型聚糖存在于 RAGE 上，RAGE 是一种有据可查的两性蛋白信号转导受体。根据我们的发现，我们假设新型聚糖可能在肿瘤生长和转移中发挥体内作用，并且 RAGE 的糖基化在肿瘤相关过程中可能很重要。因此，我们建议： 1. 建立 RAGE 上新型羧化聚糖的结构。 2. 在配体结合和细胞内信号传导方面，确定羧化聚糖在定义 RAGE 病理生理功能中的重要性。 3. 评估羧化聚糖在介导体外和体内两性蛋白-RAGE 相互作用导致肿瘤生长、侵袭和转移中的作用。对这些新型聚糖结构及其对肿瘤生长和转移的影响的基本了解可能会为正常和恶性细胞中基于碳水化合物的粘附增加一个重要维度。一种新的治疗方法也可能出现。