Sialylation in the Maintenance and Metabolic Plasticity of Neural Stem Cell-Like Brain Tumor Cells

项目概要/摘要 脑病理学研究中研究最少的领域之一是糖基化，它是大脑病理学的关键调节因子。 细胞表面蛋白质的结构和功能。 ST6Gal1 是 a2,6 唾液酸化 N-糖基化的主要酶 去往质膜或分泌物的蛋白质。唾液酸化添加了带负电荷的唾液酸 糖蛋白寡糖链的末端。不同蛋白质亚群的唾液酸化对 某些整合素、生长因子受体的构象、聚类和细胞表面保留 和死亡受体。通过这种机制，ST6Gal1 调节表型，包括生存、入侵和 干细胞维护。然而，我们对 ST6Gal1 介导的唾液酸化的理解还存在重大差距。 影响脑肿瘤细胞生长或分化状态，目前尚无研究鉴定 a2,6 唾液酸化蛋白 或 ST6Gal1 调节脑肿瘤中的通路。我们的初步数据表明，它具有新颖的促肿瘤作用 致命性脑肿瘤胶质母细胞瘤中的 a2,6 唾液酸化和 ST6Gal1。我们试图确定 ST6Gal1- 介导的 a2,6 唾液酸化促进脑肿瘤启动细胞维持和代谢可塑性。在短期内—— 从长远来看，我们的结果将有助于更好地理解 ST6Gal1 介导的 a2,6 唾液酸化如何调节蛋白质 影响脑肿瘤传播的表达和功能。从长远来看，这些研究可能会提供潜在的 ST6Gal1 抑制剂治疗脑肿瘤的治疗干预新机制正在研究中 发展。

PROJECT SUMMARY/ABSTRACT One of the least-investigated areas of research in brain pathologies is glycosylation, which is a critical regulator of cell surface protein structure and function. ST6Gal1 is the primary enzyme that a2,6 sialylates N-glycosylated proteins destined for the plasma membrane or secretion. Sialylation adds a negatively-charged, sialic acid to the end of an oligosaccharide chain of a glycoprotein. Sialylation of distinct protein subsets has important effects on conformation, clustering and cell surface retention as has been found for some integrins, growth factor receptors and death receptors. Through this mechanism, ST6Gal1 regulates phenotypes including survival, invasion, and stem cell maintenance. However, there are critical gaps in our understanding of how ST6Gal1-mediated sialylation impacts brain tumor cell growth or differentiation state, and there are no studies identifying a2,6 sialylated proteins or ST6Gal1 regulated pathways in brain tumors. Our preliminary data demonstrate a novel, pro-tumorigenic role for a2,6 sialylation and ST6Gal1 in the deadly brain tumor glioblastoma. We seek to determine whether ST6Gal1- mediated a2,6 sialylation promotes brain tumor initiating cell maintenance and metabolic plasticity. In the short- term, our results will lead to an improved understanding of how ST6Gal1-mediated a2,6 sialylation regulates protein expression and function to impact brain tumor propagation. In the long-term, these studies may offer the potential for new mechanisms of therapeutic intervention for the treatment of brain tumors as ST6Gal1 inhibitors are under development.