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 越来越多的人认识到聚糖参与了关键的小生境-细胞和细胞-细胞的通讯 信息.越来越多的证据表明，Gal（β 1，4）GlcNAc末端的β 2，6-唾液酸化，介导 通过唾液酸转移酶ST 6 Gal-1，作为调节包括细胞死亡在内的多种事件的中心参与者， 整合素-β 1功能、干细胞维持、对放射和化学试剂的敏感性、骨髓生成，以及 炎症典型地，糖基化由糖基转移酶介导，包括ST 6 Gal-1，其驻留在 在产生它们的同一细胞的内质网-高尔基体分泌器内。然而， 细胞外存在ST 6 Gal-1，尤其是在血液中。外源性ST 6 Gal-1库的变化与 患有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 通常预示着患者预后较差。 我们观察到循环中ST 6 Gal-1的缺乏导致过度旺盛的炎症反应， 这导致了细胞外ST 6 Gal-1重塑靶免疫细胞上的聚糖的总体假设， 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 和骨髓造血祖细胞是体内和体外外源性ST 6 Gal-1唾液酸化的靶标; ii） 外源性ST 6 Gal-1抑制G-CSF驱动的粒细胞生成;（iii）减少M-CSF依赖性的 （iv）减少由巨噬细胞刺激的炎性细胞因子表达和释放 LPS;和v）静脉内注射重组ST 6 Gal-1（rST 6 G）显著改善了严重的局部和局部炎症。 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 调节炎症，提出了三个目的来检查i）炎症细胞生物学的哪些方面 受外源性ST 6 Gal-1的影响; ii）外源性ST 6 Gal-1如何发挥这种作用;以及iii）疗效如何 rST 6 G在治疗严重炎症中的作用。拟议工作的影响在于 以前被忽视的外源性糖基化轴，外源性ST 6 Gal-1抑制炎症的能力， 以及重组ST 6 Gal-1治疗严重炎性病症的临床潜力的创新。