NOVEL CARBOXYLATED GLYCANS IN CELL ADHESION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 参与肿瘤生长、侵袭和转移的关键细胞过程之一是HMGB 1蛋白、白细胞介素与晚期糖基化终产物（AGEs）的细胞表面受体结合，随后激活信号转导途径。 我们发现，这种结合涉及到新的聚糖表达的β。 该提案探讨了新型聚糖的结构以及聚糖在RAGE-白细胞介素介导的信号传导事件（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。 我们发现了新的羧酸修饰内皮细胞N-连接的聚糖是完全不同的选择素配体。 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阻断小鼠的腹膜炎症。 羧化聚糖与四种蛋白质结合：三磷酸腺苷、膜联蛋白-I、S100 A8/A9和S100 A12，它们与神经突生长、肿瘤生长和转移、炎症和脓毒性休克密切相关。 我们还发现了证据表明，这些新的聚糖存在于ESTO上，ESTO是一种记录良好的ESTO信号转导受体。 基于我们的发现，我们假设新的聚糖可能在肿瘤生长和转移中具有体内作用，并且糖基化在肿瘤相关过程中可能是重要的。 因此，我们建议： 1.建立新型羧化聚糖的结构。 2.从配体结合和细胞内信号传导的角度，确定羧化聚糖在确定糖尿病的病理生理功能方面的意义。 3.评估羧化聚糖在介导体外和体内促肿瘤生长、侵袭和转移的促癌素-β-内酰胺酶相互作用中的作用。 对这些新型聚糖的结构及其对肿瘤生长和转移的影响的基本理解可能为正常和恶性细胞中基于碳水化合物的粘附增加重要维度。 一种新的治疗方法也可能出现。

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.