Regulation of IgG Sialylation

IgG 唾液酸化的调节

• 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
• 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

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。