Regulation of IgG Sialylation

IgG 唾液酸化的调节

基本信息

批准号：
10749167
负责人：
Leandre Glendenning
金额：
$ 4.13万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10749167
关键词：
Affect Affinity Anti-Inflammatory Agents Antibodies Autoimmune Autoimmune Diseases Autoimmunity Automobile Driving B-Lymphocytes Back Binding Blood Circulation Cell Line Cell surface Cells Central Nervous System Chronic Clustered Regularly Interspaced Short Palindromic Repeats Confocal Microscopy Coupled Data Disease Elements Endosomes Endothelial Cells Endothelium Environment Enzymes Fc Receptor Fc domain Glycobiology Glycoproteins Goals Golgi Apparatus HIV Half-Life Health Homeostasis Human Immune response Immunoglobulin G Immunology Immunosuppression In Vitro Incubated Infection Inflammation Inflammatory Inflammatory Response Ingestion Knock-out Knockout Mice Leadership Mammals Methods Molecular Molecular Conformation Mouse Strains Mus Pathway interactions Persons Plasma Plasma Cells Play Polysaccharides Positioning Attribute Process Reaction Recycling Regulation Regulatory Pathway Research Rheumatoid Arthritis Role Sialic Acids Sialyltransferases Signal Transduction Stimulus Tissues Training Translating Translational Research Tuberculosis United States Vesicle autoimmune inflammation career cell type chronic autoimmune disease design experience extracellular glycosylated IgG immune activation in vivo mouse model new therapeutic target novel protein function receptor binding sialylation success trafficking trans-Golgi Network

项目摘要

Project Abstract: The association between decreased plasma IgG sialylation and a variety of inflammatory diseases has been known for decades. The downstream effects of changes in IgG sialylation have been studied in depth, and it is now believed that decreases in sialylation increase the affinity of IgG for activating Fc receptors, thereby driving immune activation throughout the body. Although the downstream effects of dysregulated IgG sialylation have been well documented, the regulatory mechanisms controlling IgG sialylation remain unknown. If these mechanisms are elucidated, they may serve as novel therapeutic targets to manipulate IgG function to either enhance or suppress IgG-based inflammation, depending on the circumstances. Previous research has suggested that, unlike many other glycoproteins, IgG is not sialylated efficiently during the secretory process, pointing to a B cell-extrinsic mechanism in which IgG sialylation is dynamically regulated following its release into the bloodstream. Therefore, the goals of the proposed studies are (1) to identify key regulatory mechanisms underlying IgG sialylation and (2) to elucidate how inflammatory signals are translated into changes in the IgG glycan. The success of this study will be characterized by revealing a novel and dynamic mechanism regulating IgG function through regulated changes in glycan sialylation, while providing cutting-edge scientific and professional training that blends both glycobiology and immunology to facilitate a career trajectory focused upon leadership in IgG-based therapies and translational science.

项目摘要：血浆 IgG 唾液酸化降低与多种炎症性疾病之间的关联已被证实几十年来已为人所知。 IgG 唾液酸化变化的下游影响已得到深入研究，并且现在认为，唾液酸化的减少会增加 IgG 激活 Fc 受体的亲和力，从而驱动整个身体的免疫激活。尽管 IgG 唾液酸化失调的下游影响虽然已经有充分的记录，但控制 IgG 唾液酸化的调节机制仍然未知。如果这些机制得到阐明后，它们可能作为新的治疗靶点来操纵 IgG 功能根据情况增强或抑制基于 IgG 的炎症。先前的研究有表明，与许多其他糖蛋白不同，IgG 在分泌过程中不能有效地唾液酸化，指出 B 细胞外在机制，其中 IgG 唾液酸化在释放后受到动态调节进入血液。因此，拟议研究的目标是（1）确定关键的监管机制潜在的 IgG 唾液酸化以及 (2) 阐明炎症信号如何转化为 IgG 的变化聚糖。这项研究的成功特点是揭示了一种新颖的动态调节机制 IgG 通过聚糖唾液酸化的调节变化发挥功能，同时提供尖端的科学和技术融合糖生物学和免疫学的专业培训，以促进专注于的职业轨迹在基于 IgG 的疗法和转化科学领域处于领先地位。