IgA肾病无创诊断O-糖蛋白质的筛选及其糖基化修饰与功能的研究

IgA肾病（IgAN）是最常见的原发性肾小球疾病，其发病机制不明，且需进行肾穿刺确诊。探索IgAN的分子病理特征，实现早期无创诊断，有助于提前对其进行干预，提高治愈率。糖基化修饰尤其是O-糖基化异常是IgAN发生的关键驱动因素之一，其导致产生针对IgA1等糖蛋白的自身抗体诱导炎症反应。因此，对IgAN发生相关O-糖蛋白进行系统性研究是发现新型诊断标志物的关键。申请人前期利用自主开发的糖肽富集新材料和建立的O-糖肽质谱分析新方法，对IgAN血浆O-糖蛋白组进行了探索，初步发现几种O-糖蛋白在疾病进展更为严重的新月体IgAN中高表达，并具有更强的免疫原性。本项目拟扩大样本量并系统性筛选与IgAN发生发展相关的O-糖蛋白，通过生化方法和靶向质谱技术进行验证，并分离纯化出关键O-糖蛋白分析其糖基化修饰规律和生物学功能。项目若获实施，将有望发现无创诊断标志物，并为IgAN的靶向治疗提供分子病理依据。

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis. It needs a renal puncture diagnosis with unknown pathogenesis. Exploring the molecular pathological features and achieving early non-invasive diagnosis can help to intervene in advance and improve the cure rate of IgAN. Aberrant O-linked glycans (O-glycoproteins), is one of the most important driving reasons for the happening of IgAN, which leads to producing autoantibodies and inducing an inflammatory response. Therefore, systematic studies of O-glycoproteome are key to the discovery of novel diagnostic biomarkers. In the early stage, we have studied IgAN plasma O-glycoproteome using a new material for glycopeptides enrichment and a new method for O-glycopeptides analysis. Some O-glycoproteins express in crescentic IgAN patients with more serious disease progression and are more immunogenic. This project intends to expand the sample size, and systematically screen O-glycoproteins related to IgAN, and then corroborate by biochemical methods and targeted mass spectrometry. Further, after isolating and purifying the key O-glycoproteins, we will analyze their glycosylation change rules and roles. If fulfilled, the project will identify specific non-invasive diagnostic biomarkers and provide molecular pathology for targeted therapy of IgAN.