Group leader: Prof. Dr. Josef Pfeilschifter, Prof. Dr. Andrea Huwiler
Postdocs: PD Dr. Alexander Koch, Dr. Sandra Beyer, Dr. Stephanie Schwalm
PhD/Medical Students: Timon Eckes, Katja Jakobi (in Coop. with PD Dr. Geoergios Grammatikos), Sammy Patyna
Technicians: Dipl.-Ing. (FH) Simone Albert, Isolde Römer
Regulation of sphingolipid metabolism in cell culture and animal models of inflammatory kidney diseases.
In the last years, it has become clear that sphingolipids not only serve as inert structural components of cell membranes but may also exert important functions as signalling molecules under physiological and pathophysiological conditions. Especially ceramide and sphingosine 1-phosphate (S1P) have attracted a lot of interest due to their potential involvement in regulation of the balance between cell death and survival, particularly with regard to fibrosis and tumor growth as well as therapy. However, the mechanisms that regulate the intracellular levels of these two second messengers are still poorly understood. Ceramide itself is connected with programmed cell death (apoptosis) in many cell types. It is generated by de novo syntheses or by the salvage pathway. In the later case sphingomyelinases of which several forms have been identified are activated by a variety of stress factors. According to their pH optimum they are divided into acid, neutral and alkaline subfamilies. To date, the relevant sphingomyelinase responsible for stress-induced ceramide accumulation is not yet identified. Once generated ceramide can activate several signalling cascades that ultimately lead to apoptosis. Ceramide is degraded by ceramidases yielding sphingosine which serves as a substrate for the sphingosine kinase (SPHK)-1 and SPHK-2 to form S1P which in turn is a potent mitogen for many cell types. As it is the case for the sphingomyelinases the ceramidases are also divided into three subfamilies, the acid, neutral and alkaline forms according to their pH optimum. Particularly the neutral sphingomyelinase, the neutral ceramidase and the SPHKs, which all are predominantly found in the cytosol or at the plasma membrane, are the most likely candidates for regulating the ceramide/S1P balance in cells. We investigate neutral sphingomyelinase, neutral ceramidase, and SPHK-1 and SPHK-2 including the regulation of their expression levels and activities as well as their contribution to cell apoptosis and proliferation in vitro and in vivo. We also investigate the role of putative S1P transporter and S1P receptor activation in the context of renal diseases. A further project focuses on the analysis and quantification of various sphingolipid species from cell extracts and tissues of healthy and diseased subjects by the method of tandem mass spectrometry (in collaboration with Prof. Dr. Dr. Gerd Geisslinger, Department of Clinical Pharmacology).