Disease Pathways in Podocyte Injury - Approaching FSGS by single-nucleus RNA-sequencing

足细胞损伤的疾病途径 - 通过单核 RNA 测序探讨 FSGS

• 批准号: 433158430
• 负责人: Dr. Martin Kann
• 金额: --
• 依托单位: Lehrstuhl Systembiologie (Andreas Beyer)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/433158430?language=en
• 关键词: Disease; Pathways; Podocyte; Injury; Approaching

Podocytes are the epithelial cell-type of the renal filtration unit – the glomerulus – and podocyte disease leads to proteinuric and progressive kidney disease. The common and unifying glomerular phenotype of progressive podocyte damage and loss is focal and segmental glomerulosclerosis (FSGS). FSGS is a histologic pattern resulting from various heterogeneous and progressive disease processes that involve podocyte pathology. A hallmark of FSGS is its heterogeneity, in particular the simultaneous occurrence of various cell populations reflecting different degrees of cell damage and disease-specific molecular signatures within the same tissue. This situation is comparable to the heterogeneity of malignant tumor tissues, which may simultaneously contain tumor stem cells, differentiated and de-differentiating tumor cells, healthy cells of the host tissue, various immune cells, as well as tumor cells responding to the attacking immune system. The underlying cause of FSGS has remained elusive and the different disease entities leading to this histopathological pattern of injury are not clear. In tumor biology, single-cell and single-nucleus RNA-sequencing (scRNAseq, snRNAseq) have recently proven as powerful techniques to delineate cell populations within tumors, characterize the immune response, and understand mechanisms of resistance to tumor therapy. We have recently employed this technique to elucidate the cellular composition of the renal glomerulus (Karaiskos et al. 2018) and will now use snRNAseq to elucidate cell-specific transcriptional patterns during early pathogenesis of FSGS. Due to cellular heterogenity in the response to disease-causing stimuli in FSGS snRNAseq holds the promise to add much to the current knowledge on this disease. To reach this goal, we will employ 3 different mouse models of FSGS (one genetic model (Wt1hetdel), one toxic model (adriamycin) and one transgenic mouse model employing the podocyte-specific expression of the diphtheria toxin receptor. The data obtained will be combined with available multilayered omics-data (bulkRNAseq, proteomics, phospho-proteomics and metabolomics) to take the next towards identifying the cell biological changes underlying the pathogenesis of FSGS and to decipher cell-type specific responses in the glomerulus.

足细胞是肾脏滤过单位（肾小球）的上皮细胞类型，足细胞疾病会导致蛋白尿和进行性肾脏疾病。进行性足细胞损伤和丧失的常见且统一的肾小球表型是局灶性和节段性肾小球硬化（FSGS）。 FSGS 是一种由涉及足细胞病理学的各种异质性和进行性疾病过程引起的组织学模式。 FSGS 的一个标志是其异质性，特别是不同细胞群同时出现，反映了同一组织内不同程度的细胞损伤和疾病特异性分子特征。这种情况类似于恶性肿瘤组织的异质性，其中可能同时含有肿瘤干细胞、分化和去分化的肿瘤细胞、宿主组织的健康细胞、各种免疫细胞以及对攻击性免疫系统做出反应的肿瘤细胞。 FSGS 的根本原因仍然难以捉摸，导致这种损伤的组织病理学模式的不同疾病实体尚不清楚。在肿瘤生物学中，单细胞和单核 RNA 测序（scRNAseq、snRNAseq）最近被证明是描绘肿瘤内细胞群、表征免疫反应和了解肿瘤治疗耐药机制的强大技术。我们最近采用这种技术来阐明肾小球的细胞组成（Karaiskos et al. 2018），现在将使用 snRNAseq 来阐明 FSGS 早期发病机制期间的细胞特异性转录模式。由于 FSGS 中细胞对致病刺激的反应存在异质性，snRNAseq 有望丰富目前对该疾病的了解。为了实现这一目标，我们将采用 3 种不同的 FSGS 小鼠模型（一种遗传模型 (Wt1hetdel)、一种毒性模型（阿霉素）和一种采用白喉毒素受体足细胞特异性表达的转基因小鼠模型。获得的数据将与可用的多层组学数据（bulkRNAseq、蛋白质组学、磷酸蛋白质组学和 代谢组学）下一步旨在识别 FSGS 发病机制背后的细胞生物学变化，并破译肾小球中细胞类型的特异性反应。