Third party funded individual grant
Start date : 01.09.2018
End date : 31.08.2022
Proteinuria is a hallmark of chronic kidney disease (CKD) and an independent risk factor for kidney and cardiovascular outcomes. The dysregulation of the actin cytoskeleton in glomerular podocytes is a common pathway in the pathogenesis of proteinuria. Podocytes are highly specialized epithelial cells representing the outer surface of the glomerular filtration barrier (GFB). Defective actin dynamics in podocytes lead to the common phenotype of foot-process effacement. We recently discovered that it is possible to target the podocytic actin cytoskeleton directly using a small molecule, Bis-T-23. This compound ameliorates proteinuria and even reverses foot-process effacement and glomerular damage in highly diverse models of podocyte injury, regardless of the original cause. This finding has a fundamental impact on our current treatment concepts of proteinuria. However, since Bis-T-23 does not have characteristics necessary to become a human drug, it is necessary to identify compounds with similar biochemical and biological properties and with the ability to be directly tested in humans suffering from proteinuria. With our innovative and unique tools we have the ability to expedite the identification process and to translate these findings rapidly to clinical use. We have access to a unique comprehensive Human Blood Peptide Library for identifying native human peptides as biologically active substances. In the past many human native peptides have already been identified using focused bioassays, which are now drug candidates in various diseases and have been developed up to Phase III as putative medication. Using our unique in vitro and in vivo screening tools, with signaling defective podocytes and a high throughput proteinuria test system in zebrafish, we will identify and characterize effective peptides that restore actin cytoskeleton dynamics in podocytes with similar functional properties as Bis-T-23. These peptides could revolutionize the supportive therapy in acquired kidney diseases like diabetic nephropathy and would even -for the first time- make genetic podocyte diseases targetable. Peptides identified in this proposal that reduce proteinuria in diseased zebrafish will be further tested in rodent models of CKD and will be the basis to design a recombinant compound and plan a future clinical trial.