Unveiling the role of particulate matter (PM) and micro-/nanoplastic (MNP) in glomerular kidney disease with focus on membranous glomerulonephritis (Acronym: UNPLOK)

揭示颗粒物 (PM) 和微/纳米塑料 (MNP) 在肾小球肾病中的作用，重点关注膜性肾小球肾炎（缩写：UNPLOK）

• 批准号: 523847126
• 负责人: Professorin Dr.-Ing. Silke Christiansen
• 金额: --
• 依托单位: Medizinische Klinik 4 - Nephrologie und Hypertensiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/523847126?language=en
• 关键词: Unveiling; role; particulate; matter; PM

Membranous glomerulonephritis (MGN) is caused by autoantibodies (AABs) binding to podocyte antigens. The most frequent AAB is LA2R antibody. However, it remains unknown what triggers AAB production and how ABBs reach the subepithelial space in MGN, because the glomerular filtration barrier (GFB) is normally almost impermeable for AABs. In the past, we could show that podocyte and glomerular endothelial cell derived microRNAs (miRs) that target nephronectin - an extracellular matrix protein of the GBM produced by podocytes - might play a role in MGN. We hypothesize that particulate matter (PM) or Micro-/ nanoplastic (MNP) induce miRs that target GBM molecules enabling AABs to reach the subpodocyte space and inhibit autophagy in MGN. This hypothesis should be tested in three dimensional glomerular cell culture models, transgenic zebrafish models and mice including proteinuria and autophagy reporter lines, inducible podocyte specific miR overexpressing lines and transgenic Pla2r mice. Cell culture models as well as zebrafish and mice will be exposed to PM and MNP via cell culture medium, water and versatile aerosol concentration enrichment system. The therapeutic potential of miR antagomirs should be investigated in our zebrafish model after PM/ MNP exposure. Samples will be analyzed using miR/ mRNA arrays, Western Blot, proteinuria and autophagy assays together with a unique combination of multi-modal, scale-bridging analytics such as Raman spectroscopy, nanoGPS technology, scanning electron- and ion microscopies (FIB/SEM) and scanning ion conductance microscopy (SCICM). Kidney biopsies of patients with MGN will also be included. The comprehensive data will be correlated, quantitatively evaluated with statistical and machine learning methods and might predict future clinical diagnostic and therapeutic options.

膜性肾小球肾炎（MGN）是由自身抗体（AAB）结合足细胞抗原引起的。最常见的AAB是LA 2 R抗体。然而，它仍然是未知的触发AAB的生产和ABBs如何到达上皮下空间在MGN，因为肾小球滤过屏障（GFB）通常是几乎不可渗透的AAB。在过去，我们可以表明，足细胞和肾小球内皮细胞衍生的microRNA（miR），靶向肾连蛋白-足细胞产生的GBM的细胞外基质蛋白-可能在MGN中发挥作用。我们假设颗粒物质（PM）或微/纳米塑料（MNP）诱导靶向GBM分子的miR，使AAB能够到达足细胞下空间并抑制MGN中的自噬。这一假设应在三维肾小球细胞培养模型、转基因斑马鱼模型和小鼠（包括蛋白尿和自噬报告细胞系、可诱导足细胞特异性miR过表达细胞系和转基因Pla 2 r小鼠）中进行检验。细胞培养模型以及斑马鱼和小鼠将通过细胞培养基、水和多功能气溶胶浓度富集系统暴露于PM和MNP。应在PM/ MNP暴露后在我们的斑马鱼模型中研究miR-1200的治疗潜力。将使用miR/ mRNA阵列、蛋白质印迹、蛋白尿和自噬试验以及多模态、尺度桥接分析的独特组合（如拉曼光谱、nanoGPS技术、扫描电子和离子显微镜（FIB/SEM）和扫描离子电导显微镜（SCICM））分析样本。还将纳入MGN患者的肾活检。综合数据将被关联，并通过统计和机器学习方法进行定量评估，并可能预测未来的临床诊断和治疗选择。