权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
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
项目类别：
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

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