Focal segmental glomerulosclerosis (FSGS) is one of the most devastating glomerular diseases. Despite significant efforts to identify circulating factors, disease pathways, biomarkers and treatment targets, the discovery pipeline could not yet close the large unmet need for a better understanding and novel therapeutic solutions. We hypothesize that discoveries have been hampered by the poor clinical stratification of FSGS entities, incomplete understanding of podocyte signalling pathways and the eventually complex and low abundant nature of the predicted circulating FSGS factors. Thus, we did build a highly informative patient sample biobank of primary FSGS cases that massively recurred within the first days after renal transplant (n=45) proofing the existence of disease causing host factors. Furthermore, we generated a systematic podocyte expression atlas and signalling map of unprecedented precision and coverage. Together with the longstanding evidence that recurrent primary FSGS (rpFSGS) is being caused by immune podocyte interactions, we aim to systematically decode signalling pathways and eventual circulating factors by: (1) Characterizing pathways and secreted factors of PBMCs from rpFSGS patients. (2) Identification of podocyte signalling programs induced by rpFSGS patient serum, plasma and transferred immune cells. (3) In silico integration (and subsequent in vivo validation) of immune mediated action (aim 1) and podocyte reaction (aim 2) to predict potential FSGS factors. Collectively, these studies will provide insight into the immune-podocyte interactions, thereby facilitating the discovery of novel biomarkers and therapeutic approaches in FSGS.