Role of the podocyte adhesome in the development of FSGS

足细胞粘附体在 FSGS 发生中的作用

• 批准号: 466154718
• 负责人: Privatdozent Dr. Christoph B. Schell, Ph.D.
• 金额: --
• 依托单位: Institut für Klinische Pathologie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/466154718?language=en
• 关键词: Role; podocyte; adhesome; development; FSGS

Regardless of the underlying etiology, podocytes exhibit a uniform alteration in cellular morphology in pathological conditions of focal segmental glomerulosclerosis (FSGS). While one of the earliest detectable changes is characterized as a prominent retraction and simplification of the podocyte foot process network, increasing detachment of podocytes from the glomerular basement membrane is observed at later stages and finally results in progressive podocyte loss. These morphological observations and the identification of disease-causing mutations in adhesion genes such as ITGA3 and CD151 in the context of hereditary podocytopathies have demonstrated the outstanding relevance of the podocyte adhesion machinery. Fine-tuned adhesion of podocytes is controlled by the integrin adhesome, a multi-protein complex that is directly interconnected with the cytoskeleton. Despite significant progress, a comprehensive understanding of the adhesion-cytoskeletal nexus and its dedicated role in the pathogenesis of FSGS is lacking. The overarching goal of this proposal is to characterize dynamic alterations of the podocyte adhesome and to investigate their impact in the context of FSGS. Specifically, we will address 3 aims: (Aim 1) by combining high-resolution proteomics and multidimensional imaging approaches we will describe alterations in adhesome signatures in different stages and models of FSGS. (Aim 2) By employing novel inducible mouse models we will investigate how the central IPP complex of the adhesome controls mechano-physical adaptation of podocytes and thereby prevents podocyte detachment. (Aim 3) Finally, we will use a complementary approach based on in vitro and in vivo models to investigate the role of podocyte-specific GTPase modulators and their influence on the podocyte adhesome. In summary, our project will not only contribute to a comprehensive understanding of pathogenetic changes in the podocyte adhesion machinery in the context of FSGS but will also provide the framework for the generation of grading systems of podocyte damage which could be eventually used for stratification.

无论潜在的病因如何，在局灶节段性肾小球硬化（FSGS）的病理条件下，足细胞表现出统一的细胞形态改变。虽然最早可检测到的变化之一是足细胞足突网络的明显缩回和简化，但在晚期可以观察到足细胞从肾小球基底膜分离的增加，并最终导致进行性足细胞损失。在遗传性足细胞病变的背景下，这些形态学观察和粘附基因（如ITGA3和CD151）的致病突变的鉴定证明了足细胞粘附机制的突出相关性。足细胞的精细粘附是由整合素粘附体控制的，整合素是一种与细胞骨架直接相连的多蛋白复合物。尽管取得了重大进展，但对粘连-细胞骨架关系及其在FSGS发病机制中的作用还缺乏全面的了解。本提案的总体目标是表征足细胞粘附体的动态变化，并研究其在FSGS背景下的影响。具体来说，我们将解决3个目标：（目标1）通过结合高分辨率蛋白质组学和多维成像方法，我们将描述FSGS不同阶段和模型中粘附体特征的变化。（目的2）通过采用新型诱导小鼠模型，我们将研究粘附体的中央IPP复合体如何控制足细胞的机械-物理适应，从而防止足细胞脱离。（目的3）最后，我们将采用基于体外和体内模型的互补方法来研究足细胞特异性GTPase调节剂的作用及其对足细胞粘附体的影响。总之，我们的项目不仅有助于全面了解FSGS背景下足细胞粘附机制的发病变化，而且还将为足细胞损伤分级系统的生成提供框架，该系统最终可用于分层。