ST6Gal-1 Sialyltransferase in Inflammation

ST6Gal-1 唾液酸转移酶在炎症中的作用

• 批准号: 10265723
• 负责人: Joseph TY Lau
• 金额: $ 49.98万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265723
• 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; 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; systemic inflammatory response; 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 越来越多的人意识到葡聚糖参与了关键的生态位细胞和细胞间的通讯 信息。越来越多的证据表明，介导的Gal(1，4)GlcNAc末端的β2，6-唾液酸化 通过唾液酸转移酶ST6Gal-1，作为调节包括细胞死亡在内的各种事件的中心参与者， 整合素-1的功能、干细胞维持、对放化疗药物的敏感性、骨髓生成和 发炎。通常，糖基化是由包括ST6Gal-1在内的糖基转移酶介导的 在产生它们的相同细胞的内质网高尔基体内。然而，有相当多的 细胞外ST6Gal-1存在，尤其是在血液中。关联外部ST6Gal-1池中的更改 与应激和炎症相关的各种病理条件，以及水平升高的恶性肿瘤 通常可以预测较差的患者结果。 我们观察到，循环中ST6Gal-1的缺乏会导致过度活跃的炎症反应， 这导致了一个重要的假设，即细胞外ST6Gal-1重塑了靶免疫细胞上的多糖 表面，抑制对炎症信号的反应。支持的其他前提是：i)成熟的髓系 在体内和体外，骨髓造血祖细胞是外源性ST6Gal-1唾液酸化的靶点； 外源性ST6Gal-1抑制G-CSF驱动的粒细胞生成；(Iii)减少对M-CSF依赖的生成 巨噬细胞；(Iv)减少炎症细胞因子的表达和释放 静脉注射重组ST6Gal-1(RST6G)显著改善严重的局部和 体内的全身性炎症。为了深入了解以前被忽视的糖基化反应 炎症的调节，提出了三个目标来研究i)炎症细胞生物学的哪些方面 受外源性ST6Gal-1的影响；ii)外源性ST6Gal-1是如何发挥这一作用的；以及iii)疗效是什么 RST6G在治疗重症炎症中的作用拟议工作的影响在于其新颖性 以前忽略了外源性糖基化轴，外源性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。

项目成果

Computational studies on glycosaminoglycan recognition of sialyl transferases.

唾液酸转移酶糖胺聚糖识别的计算研究。

• DOI: 10.1093/glycob/cwad040
• 发表时间: 2023
• 期刊: Glycobiology
• 影响因子: 4.3
• 作者: Sankaranarayanan,NehruViji;Sistla,Srinivas;Nagarajan,Balaji;Chittum,JohnE;Lau,JosephTY;Desai,UmeshR
• 通讯作者: Desai,UmeshR