ST6Gal-1 Sialyltransferase in Inflammation

ST6Gal-1 唾液酸转移酶在炎症中的作用

• 批准号: 10230376
• 负责人: Joseph TY Lau
• 金额: $ 49.67万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230376
• 关键词: Acute; Affect; Anti-Inflammatory Agents; Attenuated; Awareness; Bacteria; Biological; Blood; CSF3 gene; Cell Death; Cell Maintenance; Cell surface; Cells; Cellular biology; Clinical; Communication; Data; Development; Distal; Effectiveness; Estrogen receptor positive; Event; Generations; Glycobiology; Goals; Golgi Apparatus; Granulopoiesis; Hematopoietic stem cells; Human; Immune Targeting; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Integrins; Intervention; Left; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Marrow; Mediating; Modeling; Mus; Myelogenous; Myeloid-derived suppressor cells; Myelopoiesis; Pathologic; Pathway interactions; Patient-Focused Outcomes; Phenotype; Physiological; Polysaccharides; Predisposition; Production; Property; Radio; Recombinants; Regulation; Sepsis; Sialyltransferases; Signal Transduction; Stimulus; Stress; Survivors; Syndrome; Testing; Therapeutic; Time; Work; acute symptom; airway inflammation; base; cytokine; extracellular; glycosylation; glycosyltransferase; in vivo; innovation; insight; intravenous administration; intravenous injection; macrophage; mortality; mouse model; novel; protective effect; recruit; response; sialylation; stem cells; therapeutic development

PROJECT ABSTRACT There is increasing awareness of glycans participating in the communication of critical niche-cell and cell-cell information. A growing body of evidence implicates the 2,6-sialylation of Gal(β1,4)GlcNAc termini, mediated by the sialyltransferase ST6Gal-1, as a central player in the regulation of diverse events including cell death, integrin-1 function, stem cell maintenance, susceptibility to radio- and chemo-agents, myelopoiesis, and inflammation. Canonically, glycosylation is mediated by glycosyltransferases, including ST6Gal-1, residing within the ER-Golgi secretory apparatus of the same cells that produce them. However a significant pool of extracellular ST6Gal-1 exists, especially in the blood. Changes in the extrinsic ST6Gal-1 pool are associated with diverse pathologic conditions relating to stress and inflammation, and malignancies where elevated levels generally predict poorer patient outcomes. We observed that deficiency in circulating ST6Gal-1 results in an overly exuberant inflammatory response, which led to the overarching hypothesis that extracellular ST6Gal-1 remodels glycans on target immune cell surfaces, dampening response to inflammatory signals. Additional premise in support are: i) mature myeloid and marrow hematopoietic progenitor cells are targets of extrinsic ST6Gal-1 sialylation in vivo and in vitro; ii) extrinsic ST6Gal-1 suppresses G-CSF driven granulopoiesis; (iii) reduces M-CSF dependent generation of macrophages; (iv) decreases inflammatory cytokine expression and release by macrophage stimulated with LPS; and v) intravenous injection of recombinant ST6Gal-1 (rST6G) significantly ameliorates severe local and systemic inflammation in vivo. To acquire insight into this previously overlooked glycosylation mediated regulation of inflammation, three aims are proposed to examine i) which aspects of inflammatory cell biology are affected by extrinsic ST6Gal-1; ii) how does extrinsic ST6Gal-1 exert this action; and iii) what is the efficacy of rST6G in treating severe inflammation. The impact from the proposed work lies in the novelty of the previously overlooked extrinsic glycosylation axis, the ability of extrinsic ST6Gal-1 to suppress inflammation, and the innovation in the clinical potential of recombinant ST6Gal-1 to treat severe inflammatory conditions.

项目摘要 人们越来越认识到聚糖参与关键的微环境细胞和细胞间的通讯 信息。越来越多的证据表明 Gal(β1,4)GlcNAc 末端的 α2,6-唾液酸化介导 唾液酸转移酶 ST6Gal-1 作为细胞死亡等多种事件调节的核心角色， 整合素-1 功能、干细胞维持、对放射和化疗药物的敏感性、骨髓生成和 炎。通常，糖基化是由糖基转移酶介导的，包括 ST6Gal-1， 在产生它们的相同细胞的内质网高尔基体分泌装置内。然而，有相当数量的 细胞外存在ST6Gal-1，尤其是在血液中。外在 ST6Gal-1 池的变化与之相关 与压力和炎症相关的多种病理状况，以及水平升高的恶性肿瘤 通常预测患者的预后较差。 我们观察到循环 ST6Gal-1 的缺陷会导致过度旺盛的炎症反应， 这导致了一个总体假设：细胞外 ST6Gal-1 重塑靶免疫细胞上的聚糖 表面，抑制对炎症信号的反应。支持的其他前提是：i) 成熟的骨髓细胞 骨髓造血祖细胞是体内和体外外源性 ST6Gal-1 唾液酸化的靶标；二） 外源性 ST6Gal-1 抑制 G-CSF 驱动的粒细胞生成； (iii) 减少 M-CSF 依赖性生成 巨噬细胞； (iv) 减少巨噬细胞刺激的炎性细胞因子表达和释放 脂多糖； v) 静脉注射重组 ST6Gal-1 (rST6G) 显着改善严重的局部和 体内全身性炎症。为了深入了解这种以前被忽视的糖基化介导的 炎症的调节，提出了三个目标来检查 i) 炎症细胞生物学的哪些方面 受外源性 ST6Gal-1 影响； ii) 外源性 ST6Gal-1 如何发挥这种作用； iii) 功效是什么 rST6G 治疗严重炎症。拟议工作的影响在于其新颖性 以前被忽视的外在糖基化轴，外在 ST6Gal-1 抑制炎症的能力， 以及重组 ST6Gal-1 治疗严重炎症的临床潜力的创新。