The role of CD2AP-interacting proteins in the pathogenesis of focal segmental glomerulosclerosis - an in vivo screening approach

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Although the focal segmental glomerulosclerosis (FSGS) is the most frequent glomerulopathy of the adult and one of the major reasons for end-stage renal disease, its pathomechanisms are poorly understood. One of the proteins that plays a major role in the development of FSGS is the slit diaphragm associated CD2AP. The aim of this project is the functional characterization of 22 interactors of CD2AP in the pathogenesis of FSGS. To this end, shRNAs against the previously identified candidate genes will be expressed in an inducible and podocyte-specific way in mice that are heterozygous for CD2AP and synaptopodin. These mice have been shown to exhibit an increased susceptibility for the development of FSGS. A revolutionary technique makes it possible to generate 100% transgenic mice directly from ES cells. These animals will be screened for proteinuria, to identify candidates that play a role in the development of the disease. The identified proteins will be characterized in vivo by urine analysis and histology including electron microscopy. Isolated podocytes will be analyzed by different molecular and cell biological techniques including interaction studies with slit diaphragm proteins and components of the actin cytoskeleton to identify new therapeutic targets. More specific and individualized therapeutic strategies are the key to prevent end stage renal disease and dialysis treatment for our patients.