ST6Gal-1 Sialyltransferase in Inflammation

ST6Gal-1 唾液酸转移酶在炎症中的作用

基本信息

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
项目类别：
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

项目摘要

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越来越多的证据表明 Gal(β1,4)GlcNAc 末端的 α2,6-唾液酸化作用是介导的。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，但是有一个重要的池。细胞外 ST6Gal-1 的存在，尤其是在血液中，与外源性 ST6Gal-1 池的变化相关。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 的缺乏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 ii) 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； (iv) 减少巨噬细胞刺激的炎性细胞因子表达和释放 LPS；和 v) 静脉注射重组 ST6Gal-1 (rST6G) 显着改善严重的局部和深入了解这种以前被忽视的糖基化介导的过程。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到外源性 ST6Gal-1 的影响；ii) 外源性 ST6Gal-1 如何发挥这种作用，以及 iii) 功效是什么？ rST6G 治疗严重炎症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。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Blood-Borne ST6GAL1 Regulates Immunoglobulin Production in B Cells.

血源性 ST6GAL1 调节 B 细胞中免疫球蛋白的产生。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Irons, Eric E;Punch, Patrick R;Lau, Joseph T Y
通讯作者：
Lau, Joseph T Y

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：
发表时间：
2023-08-14
期刊：
影响因子：
4.3
作者：
Sankaranarayanan, Nehru Viji;Sistla, Srinivas;Nagarajan, Balaji;Chittum, John E;Lau, Joseph T Y;Desai, Umesh R
通讯作者：
Desai, Umesh R