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KFO 329:  Disease pathways in podocyte injury – from molecular mechanisms to individualized treatment options

Subject Area Medicine
Term since 2018
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 386793560
 
More than 200 million persons worldwide suffer from chronic kidney diseases (CKD). Glomerular disorders account for the majority of cases of CKD. Podocyte injury is central to the development of many different glomerular diseases. Even in normal ageing podocyte loss contributes to age-related decline in renal function. Landmark genetic studies identified hereditary mutations in genes expressed by glomerular podocytes as cause of proteinuria, progressive glomerulosclerosis and end-stage renal disease. These studies initiated a spurt of research that profoundly changed our view of the glomerular filtration barrier and the role of podocyte injury in the development of glomerular disease. Alterations of various independent signaling pathways cause podocyte dysfunction and loss leading to the development of focal and segmental glomerulosclerosis (FSGS) in experimental animals. Unfortunately, the remarkable advance in the understanding of glomerular biology has not yet resulted in better treatment options for patients with podocyte disease such as FSGS and treatment alternatives in patients with steroid-resistant forms of FSGS are still scarce. This CRU is based on the understanding that (primary) FSGS is not a uniform disease entity, but represents a histopathological pattern of injury resulting from many different causative disease mechanisms. However, distinguishing different pathophysiological entities and their specific molecular and cell biological disease-causing mechanisms is key to the development of novel targeted therapeutic strategies. Here, we will combine forces to translate pathophysiological principles studied in mice and newly identified genomic alterations in patients into new diagnostic and therapeutic tools. We will study distinct disease pathomechanisms of podocyte injury, ranging from alterations of slit diaphragm signaling, over cytoskeletal rearrangements, the deregulation of transcriptional networks and non-coding RNA molecules to mitochondrial and metabolic dysfunction and defective immune and stress signaling, to (1) provide a better understanding of individual disease pathomechanisms in podocyte disease, (2) identify markers of these alterations for diagnostics, (3) develop potential tailored therapeutic interventions, based on the pathophysiologic understanding of podocyte disorders in individual patients. The ultimate aim is to be able to diagnose and treat distinctly deregulated pathways in podocyte disease with a tailored approach, i.e. a precision medicine strategy. From the very beginning the Center for Clinical Trials at the University Hospital Cologne will be involved to establish a national registry for renal biopsy, blood and urine samples together with clinical data. We are convinced that this approach will ultimately result in practice-changing research that leads to a new mechanism-based classification of FSGS and allows tailored new treatment options and individualized treatment approaches.
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