Novel Carboxylated Glycans in Cell Adhesion

细胞粘附中的新型羧化聚糖

• 批准号: 6605622
• 负责人: Hudson H. Freeze
• 金额: $ 35.24万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6605622
• 关键词: SCID mouse; amides; animal tissue; binding sites; biological signal transduction; carbohydrate analog; carbohydrate structure; carboxylation; cell adhesion; cell line; crosslink; dicarboxylate; glycation; immunoglobulins; monoclonal antibody; neoplastic growth; neuroblastoma; oligosaccharides; protein binding; protein protein interaction; receptor

DESCRIPTION (provided by applicant): Malignancy involves cellular growth, movement, and metastasis. One of the key cellular check-points regulating these features is the binding of a secreted cytosolic molecule called amphoterin to the cell surface receptor for advanced glycation end products (RAGE). We found that this binding involves novel glycans that we discovered. This proposal explores the structure and function of the glycans that mediate these interactions. We have identified a new type of carboxylated N-linked oligosaccharide that is especially enriched in endothelial cells, embryonic neurons and cancer cells. Our biochemical and immunological evidence indicates that the antigen contains di-carboxylated amino acids amide-linked to the sugar chains. These novel glycans mediate endothelium/leukocyte binding, and intraperitoneal inflammation in vivo and neurite outgrowth in vitro. The carboxylated glycans directly bind to four proteins: amphoterin, annexin-I and S 100A8/A9, and S100A12, which have been linked in various ways to inflammation, septic shock, tumor growth or metastasis. We found that RAGE N-linked sugar chains contain the carboxylates and that they mediate amphoterin-RAGE binding and some of the multiple intracellular signaling events they ignite. To understand the role of the carboxylated glycans in this complex process, we propose to: 1. Establish the detailed structure of the carboxylated glycans on bovine RAGE and in neuroblastoma cells. 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 that lead 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 the understanding of these pathologies and may lead to novel therapeutic approaches to block them.

描述（由申请人提供）：恶性肿瘤涉及细胞生长，运动和转移。调节这些特征的关键细胞检查点之一是一种被称为大二苯蛋白与细胞表面受体的分泌的胞质分子的结合，以进行晚期糖基化末端产物（RAGE）。我们发现这种结合涉及我们发现的新型聚糖。该建议探讨了介导这些相互作用的聚糖的结构和功能。我们已经确定了一种新型的羧化N-连接寡糖，该寡糖在内皮细胞，胚胎神经元和癌细胞中特别富集。我们的生化和免疫学证据表明，抗原含有二羧化氨基酸酰胺与糖链连接的氨基酸。这些新型的聚糖介导了体内和神经突在体内生长体内的内皮/白细胞结合，并介导腹膜内炎症。羧化的甘氨酸直接与四种蛋白质结合：两栖动物，膜联蛋白I和S 100A8/A9和S100A12，它们以各种方式连接到炎症，败血性休克，肿瘤生长或转移。我们发现，愤怒的N连接糖链含有羧酸盐，并且它们介导了两性链林的结合以及它们点燃的一些多个细胞内信号传导事件。为了了解羧化聚糖在这一复杂过程中的作用，我们建议： 1。在牛愤怒和神经母细胞瘤细胞中建立羧化聚糖的详细结构。 2。确定羧化聚糖在定义愤怒的病理生理功能的显着性，从配体结合和细胞内信号传导方面。 3。评估羧化糖在体外和体内介导两半相互作用中的作用，从而导致肿瘤的生长，侵袭和转移。对这些新型聚糖的结构的基本了解，以及它们对肿瘤生长和转移的影响，可能会使对这些病情的理解增加对他们的理解，从而使他们的理解为新颖的病态而引起。