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性疾病之间的关联， 几十年前就知道了。已经深入研究了IgG唾液酸化变化的下游影响， 现在认为唾液酸化的减少增加了IgG对激活Fc受体的亲和力，从而 驱动全身的免疫激活。尽管IgG唾液酸化失调的下游效应 尽管已经有充分的文献记载，但控制IgG唾液酸化的调节机制仍然未知。如果这些 机制阐明，它们可以作为新的治疗靶点，以操纵IgG功能， 增强或抑制基于IgG的炎症，这取决于情况。先前的研究 表明，与许多其他糖蛋白不同，IgG在分泌过程中不被有效地唾液酸化， 表明IgG唾液酸化在其释放后被动态调节的B细胞外源性机制 进入血液。因此，建议研究的目标是（1）确定关键的调节机制 潜在的IgG唾液酸化和（2）阐明炎症信号如何转化为IgG的变化 聚糖。这项研究的成功将揭示一个新的和动态的机制， 通过调节聚糖唾液酸化的变化来发挥IgG功能，同时提供尖端的科学和 专业培训，融合糖生物学和免疫学，以促进职业生涯的轨迹集中在 在IgG为基础的治疗和转化科学的领导地位。