CRC TRR 422: Podocyte Signaling Networks - From Basic Concepts to Disease Understanding (PodoSigN)

Basic data for this project

Description

Podocytes form an integral part of the kidney's filtration system. They cover the outer surface of the glomerular basement membrane (GBM), closely enveloping the glomerular capillaries to facilitate the ultrafiltration of fluids, maintaining the body's internal equilibrium. These cells are particularly susceptible to injuries stemming from genetic, hemodynamic, metabolic, inflammatory, and environmental factors. Their inability to undergo cell division underscores the imperative of preserving their transcriptome, proteome, and metabolome balance throughout an organism's lifespan. Biologically, podocytes are characterized by their exquisite differentiation, adaptive responses to external signals, intricate cytoskeletal organization, and complex integrated signaling networks. From a medical perspective, the loss of podocytes plays a critical role in the most prevalent forms of chronic kidney disease (CKD). The severity of symptoms, such as albuminuria, directly corresponds to podocyte damage. Even though we know about the importance of podocyte health, therapeutic strategies still fail to address podocyte-specific diseases. Currently, the field suffers from stagnation of therapeutic developments, paired with a critically high rate of unsuccessful trials. We hypothesize that the incomplete comprehension of podocyte physiology is responsible for the lack of bench-to-bedside translation. To change this, we need to understand the complex balance of health- and injury signaling at the level of structural organization, cellular homeostasis, genetic programs, and metabolism. Recent advancements in molecular and spatial (single-cell) techniques, combined with (AI-driven) computational analytics, now enable research to advance kidney and podocyte knowledge at the complexity and integration required for next-level podocyte precision medicine. Our teams have pioneered advancements in single-cell analysis, omics technologies, multiplex imaging, and computational analytics in podocyte research. In our joint effort, we aim to systematically decode podocyte signaling maps, identify disease checkpoints, and generate knowledge graphs, integrating this information with data from our extensive national and European glomerulopathy tissue repositories. This transregional Collaborative Research Center (CRC) brings together leading experts in podocyte research from diverse disciplines, including medicine, biology, chemistry, genetics, computational science, and mathematics. Together, we will transform our understanding of podocyte-related diseases. Our 12-year perspective is to deepen the understanding of the signaling landscape of podocyte health and injury signaling (phase 1), develop integrated genome/proteome/metabolome-scale models of podocyte disease, including validated disease checkpoints (phase 2), and ultimately improve podocyte and kidney health based on targeted intervention and drug repurposing strategies (phase 3).