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Glycoengineering IgA1 in IgA nephropathy

IgA 肾病中的糖工程 IgA1

基本信息

批准号：
10179319
负责人：
Robert McCullough Anthony
金额：
$ 25.08万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2020-06-03 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10179319
关键词：
Acetylgalactosamine Antibodies Antigen-Antibody Complex Attenuated Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Binding CD209 gene Cell Proliferation Complement Deposition Development Disease Doctor of Philosophy Effector Cell End stage renal failure Engineering Enzymes Epitopes Functional disorder Galactose Generations Glomerulonephritis Health Homeostasis Human IGA Glomerulonephritis IgA1 IgE IgG autoantibodies IgG1 Immune Immune response Immunodeficient Mouse Immunoglobulin A Immunoglobulin G Inflammation Intravenous Kidney Lead Link Masks Mediating Modeling Molecular Conformation Mus Pathogenicity Patients Play Polysaccharides Process Protocols documentation Recombinant Fusion Proteins Regimen Regulation Rheumatoid Arthritis Role Severities Sialic Acids Structure Techniques Testing Therapeutic glycosylated IgA glycosylation glycosyltransferase high reward high risk in vivo mesangial cell mouse model novel novel strategies prevent response sialylation treatment strategy

项目摘要

ABSTRACT IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and often progresses to end stage renal disease due to the absence of disease-specific modifying therapies. Unlike many other autoimmune diseases, an autoantigen in IgAN has been identified and characterized. Altered O-glycosylation in the heavy chain of IgA1 exposes antigenic determinants, which are targets of naturally occurring IgG1 and, to a lesser extent, IgA1 antibodies. The resulting circulating immune complexes together with complement deposit in the kidney to promote mesangial cell proliferation and matrix expansion, which in turn induce glomerular dysfunction. The objective of this proposal is to develop novel glycoengineering techniques to restore glycosylation of the IgA and thus inhibit its autoantigenicity. Successful completion of this proposal could lead to the development of a new disease-specific therapeutic strategy for the treatment of IgA. This is a high-risk proposal as there are conceivable pitfalls with developing the techniques for restoring glycosylation. The high-reward is the potential to normalize IgA1 glycan structures and thus avert the generation and subsequent deposition of pathogenic IgA1-anti-IgA1 immune complexes and associated glomerulonephritis.

摘要伊加肾病（IgAN）是世界范围内最常见的原发性肾小球肾炎，并且通常进展为终末期肾病，由于缺乏疾病特异性修饰疗法。不像许多其他在自身免疫性疾病中，IgAN中的自身抗原已被鉴定和表征。O-糖基化改变在IgA 1的重链中暴露抗原决定簇，这些抗原决定簇是天然存在的IgG 1 以及较小程度的IgA 1抗体。产生的循环免疫复合物与补体存款在肾脏，以促进系膜细胞增殖和基质扩张，这反过来引起肾小球功能障碍。该提案的目的是开发新的糖工程技术来恢复伊加的糖基化，从而抑制其自身抗原性。成功完成这一建议可能导致开发一种新的疾病特异性治疗策略，的伊加。这是一个高风险的建议，因为在开发用于恢复糖基化。高回报是使IgA 1聚糖结构正常化的潜力，从而避免致病性IgA 1-抗IgA 1免疫复合物的产生和随后的沉积以及相关的肾小球肾炎