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

项目概要/摘要 脑病理学研究中最少研究的领域之一是糖基化，其是脑组织中糖基化的关键调节因子。 细胞表面蛋白质的结构和功能。ST 6 Gal 1是α 2，6唾液酸化N-糖基化的主要酶 预定用于质膜或分泌的蛋白质。唾液酸化将带负电荷的唾液酸添加到 糖蛋白寡糖链的末端。不同蛋白质亚群的唾液酸化对蛋白质合成具有重要影响。 构象，聚集和细胞表面保留，如已经发现的一些整合素，生长因子受体 和死亡感受器通过这种机制，ST 6 Gal 1调节表型，包括存活、侵袭和免疫应答。 造血干细胞然而，我们对ST 6 Gal 1介导的唾液酸化作用的理解存在关键性的差距， 影响脑肿瘤细胞生长或分化状态，目前还没有研究发现a2，6唾液酸化蛋白 或ST 6 Gal 1调节的途径。我们的初步数据表明， α 2，6唾液酸化和ST 6 Gal 1在致命的脑肿瘤胶质母细胞瘤中的作用。我们试图确定ST 6 Gal 1- 介导的α 2，6唾液酸化促进脑肿瘤起始细胞维持和代谢可塑性。简而言之- 我们的研究结果将有助于进一步了解ST 6 Gal 1介导的α 2，6唾液酸化是如何调节蛋白质表达的 表达和功能来影响脑肿瘤的传播。从长远来看，这些研究可能会提供 用于治疗脑肿瘤的治疗性干预的新机制，因为ST 6 Gal 1抑制剂正在 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.