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Quantitative Analysis of Serum Autoantibody Repertories in Systemic Lupus Erythematosus

系统性红斑狼疮血清自身抗体库的定量分析

基本信息

批准号：
10513812
负责人：
Kenneth Michael Smith
金额：
$ 40.44万
依托单位：
UNIVERSITY OF OKLAHOMA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-15 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10513812
关键词：
3-Dimensional Affect Affinity Chromatography American Antibodies Antigens Arthralgia Autoantibodies Autoantigens Autoimmune Diseases Bioinformatics Biological Markers Blood Blood capillaries Complex Mixtures Development Disease Progression Electrophoresis Enzyme-Linked Immunosorbent Assay Epitope spreading Exanthema Foundations Goals Immunoglobulin G Immunology Intervention Label Light Link Mass Spectrum Analysis Methods Monoclonal Antibodies Organ Pathogenicity Patients Pharmaceutical Preparations Prevention Process Production Prognosis Proteins Proteomics Recombinants Research Research Personnel Resources Sampling Serum Sjogren&apos s Syndrome Symptoms Systemic Lupus Erythematosus Testing Time Work advanced analytics analytical tool antigen binding bioinformatics tool biomarker discovery biomarker identification biomarker validation diagnostic platform diagnostic value human monoclonal antibodies mortality novel pressure prevent proteogenomics systemic autoimmune disease ultra high pressure

项目摘要

SUMMARY Systemic Lupus Erythematosus (SLE) is a multi-organ, systemic autoimmune disorder, estimated to affect at least 1.5 million Americans. The hallmark of SLE is the production of serum autoantibodies, a unifying feature present in over 99% of untreated patients. Such autoantibodies are directly pathogenic, eventually causing the symptoms of SLE including debilitating joint pain and rashes, followed by organ damage and early mortality. Previous work has shown that autoantibodies begin to accrue months to years before the symptoms of SLE appear which may allow a window for detecting them and starting medications to prevent or at least delay the onset of SLE. These serum autoantibodies, however, consist of a complex mixture in the blood including pathogenic, non-pathogenic, and beneficial antibodies which may number in the millions. While current diagnostic platforms can screen for total autoantibodies during autoimmune disease, finding specific monoclonal autoantibodies linked to the development of SLE is currently impossible. Thus, the lack of capability to directly detect monoclonal, pathogenic, autoantibodies presents a significant barrier in understanding how autoantibodies arise, and there is a critical need to develop advanced analytical tools to characterize these antibodies. Our long-term goal is to understand SLE autoantibody development at the monoclonal level and to develop high diagnostic value autoantibody biomarkers. The overall objective of this proposal to establish a novel integrated proteomics platform that employs two complementary scientific approaches, a quantitative top-down MS approach for autoantibody biomarker discovery, and a top-down proteogenomics sequencing approach for autoantibody biomarker validation and functional characterization. Our proposed top-down autoantibody proteomics platform will be applied to identify intact autoantibody Fab signatures in longitudinal SLE serum samples. As a result, we will provide a first top-down proteomics platform for characterizing SLE autoantibodies at the monoclonal level. Applying it to the analysis of SLE autoantibodies will provide foundations for new strategies in SLE prognosis, intervention, and prevention, and may lead to novel high diagnostic value biomarkers. After development, our top-down autoantibody characterization platform can be easily adapted to other autoimmune diseases such as Sjogren’s Syndrome.

总结系统性红斑狼疮（SLE）是一种多器官、系统性自身免疫性疾病，估计影响约100万人。至少150万美国人SLE的标志是产生血清自身抗体，在99%以上的未治疗患者中存在。这种自身抗体是直接致病的，最终导致 SLE的症状包括使人虚弱的关节疼痛和皮疹，随后是器官损伤和早期死亡。以前的研究表明，自身抗体开始积累数月至数年前的症状系统性红斑狼疮这可能会允许一个窗口来检测它们并开始药物治疗，以防止或至少延迟 SLE的发病。然而，这些血清自身抗体由血液中的复杂混合物组成，包括致病性、非致病性和有益的抗体，其数量可达数百万。虽然目前的诊断平台可以在自身免疫性疾病期间筛查总自身抗体，单克隆自身抗体与SLE的发展有关目前是不可能的。因此，缺乏直接检测单克隆、致病性、自身抗体的能力是一个重要的障碍，了解自身抗体是如何产生的，迫切需要开发先进的分析工具，描述这些抗体。我们的长期目标是了解SLE自身抗体的发展，单克隆水平，并开发高诊断价值的自身抗体生物标志物。本报告的总体目标建议建立一个新的综合蛋白质组学平台，采用两个互补的科学方法，用于自身抗体生物标志物发现的定量自上而下的MS方法，以及用于自身抗体生物标志物发现的自上而下的MS方法。蛋白基因组学测序方法用于自身抗体生物标志物验证和功能表征。我们提出的自上而下的自身抗体蛋白质组学平台将用于鉴定完整的自身抗体Fab 纵向SLE血清样本中的特征。因此，我们将提供第一个自上而下的蛋白质组学平台用于在单克隆水平上表征SLE自身抗体。将其应用于SLE的分析自身抗体将为SLE预后、干预和预防的新策略提供基础，可能导致新的高诊断价值的生物标志物。经过开发，我们的自上而下的自身抗体该表征平台可以容易地适用于其他自身免疫性疾病，如干燥综合征。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Nanoparticle Surface Engineering with Heparosan Polysaccharide Reduces Serum Protein Adsorption and Enhances Cellular Uptake.

DOI：
10.1021/acs.nanolett.2c00349
发表时间：
2022-03-09
期刊：
NANO LETTERS
影响因子：
10.8
作者：
Yang, Wen;Wang, Lin;Fang, Mulin;Sheth, Vinit;Zhang, Yushan;Holden, Alyssa M.;Donahue, Nathan D.;Green, Dixy E.;Frickenstein, Alex N.;Mettenbrink, Evan M.;Schwemley, Tyler A.;Francek, Emmy R.;Haddad, Majood;Hossen, Md Nazir;Mukherjee, Shirsha;Wu, Si;DeAngelis, Paul L.;Wilhelm, Stefan
通讯作者：
Wilhelm, Stefan

High-throughput quantitative top-down proteomics.