DNCURE · Dynamic signalling networks in Diabetic Nephropathy (DN) – New avenues to a personalized therapy.-

Dynamic signalling networks in Diabetic Nephropathy (DN) – New avenues to a personalized therapy.-We have developed an exquisite experimental platform that facilitates the systematic unravelling of the signallingnetworks leading to (1) the initiation, (2) the progression and (3) the potential regeneration of podocytes inDN, paving the way to novel therapeutic strategies:(1) DN initiation: Identification of signalling cascades leading to microalbuminuria: MolecularBy combining transgenic Drosophila lines carrying secreted fluorescent proteins to monitor the barrier functionin vivo with a genome-wide siRNA screen we will establish a unique system to directly identify genenetworks contributing to microalbuminuria.(2a) DN progression: Molecular fingerprinting of podocyte degeneration: Based on a transgenicfluorescent mouse model, we have pioneered a highly efficient podocyte purification method from type1 andtype 2 diabetic mice allowing us to develop a precise molecular genetic, quantitative proteomic and microRNA fingerprint from freshly isolated podocytes from diabetic and non-diabetic mice.(2b) DN progression: We established a proteomic approach to measure site-specific phosphorylation dynamics inprimary podocyte cultures originating from transgenic mice that are TORC1 deficient, TORC2 deficient orTORC1 hyperactive (TSC1 KO) solely in the podocytes.(3) Potential role of podocyte regeneration in DN: Finally, to target mechanisms that could potentiallyreverse the disease process (by repopulating lost podocytes), we invented a strategy to quantitatively monitorpodocyte turnover from different stem cell niches allowing us to precisely assess and potentiallymanipulating the capacity of podocyte regeneration in DN.