Novel inhibitors of neutral and acid ceramidases and their application in experimental therapies of inflammatory and proliferative kidney diseases

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The cellular equilibrium between ceramide and sphingosine-1-phosphate plays a key role in functional cellular responses like cell differentiation, cell growth and cell death as well as in some aspects of inflammatory events. This cellular “sphingolipid rheostat” is primarily regulated by three classes of enzymes: The ceramide generating sphingomyelinases, the ceramide degrading ceramidases and finally the sphingosine kinases. Our aim is to develop and synthesize novel inhibitors of the different ceramidases. We plan to test the substances in in vitro tests using recombinant human and murine enzymes. Afterwards, the cellular activity will be assessed with regards on cellular ceramidase activites, on cellular lipid concentrations and on cellular responses like cell-proliferation and apoptosis. Glomerulonephritis is a chronic inflammatory kidney disease in which hyperproliferation is an important aspect. We plan to test novel ceramidase inhibitors in cellular assays for inflammatory and hyperproliferative kidney diseases, but also in cancer cells. Finally promising candidates will be used for experimental therapies employing cellular and in vivo models of glomerulonephritis and cancer.