SPP 1267:  Sphingolipids - Signals and Disease

• Subject Area: Medicine ; Biology
• Term: from 2007 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 25760443

Sphingolipids were thought for long time to be structural elements of the cell membrane and even in the 1980s a signalling function of these compounds was unknown. Between 1990 and 1995 several important discoveries on the biological role of sphingolipids were achieved resulting in a change of paradigms. These studies revealed an important function of sphingolipds, in particular ceramide, sphingosine and sphingosine-1-phosphate, in basic mechanisms of biology, for instance cell death, cell differentiation, migration, angiogenesis and embryonal development. It was discovered that sphingolipids are also major players in many human disorders, e.g. neuro-degenerative diseases (e.g. M. Alzheimer), ischemic tissue damage (e.g. heart attack, stroke), atherosclerosis, bacterial, viral and parasitic infections, sepsis, cystic fibrosis, psoriasis, glomerulosclerosis, autoimmune disorders and malignant tumours.
The discovery of the drug FTY720 that interferes with sphingosine-1-phosphate highlights the potential of sphingolipids as novel therapeutic targets to achieve effective immune suppression upon organ transplantation, in multiple sclerosis or rheumatoide arthritis.
The Priority Programme has the following aims:
(1) Characterisation of the basic mechanisms that regulate enzymes involved in sphingolipid metabolism and mediate the physiological and pathophysiological functions of sphingolipids.
(2) Translation of insights from basic science on the cellular regulation and function of sphingolipids into novel treatment strategies. In particular, the Priority Programme aims to develop novel strategies to treat infectious diseases, disorders of the cardio-renovascular system and tumours. Furthermore, we are aiming to selectively target the immune system via a manipulation of sphingolipids. Examples of important diseases that are investigated in the Priority Programme are bacterial pneumonia, sepsis, cystic fibrosis, atherosclerosis, cardiomyopathies, renal fibrosis, glomerulosclerosis, malignant tumours and M. Alzheimer.
(3) Establishment of a structure and network of groups that are investigating sphingolipids. In particular we want to promote an interdisciplinary network of basic and clinical scientists to translate molecular insights into the structure and function of sphingolipids into novel clinical treatments.
(4) Intense scientific training and promotion of young scientists, PhD students and postdocs from both basic and clinical sciences in the field of sphingolipid research. Further, we are aiming to attract young scientists worldwide to establish a group in Germany studying sphingolipids.
(5) Finally, we are aiming to establish and promote cooperation between universities and pharmaceutical industry.

• DFG Programme: Priority Programmes
• International Connection: Switzerland

Projects

• Acid Sphingomyelinase Inhibition protects against experimental Multiple Sclerosis: mechanisms and translation to therapy (Applicant Fassbender, Klaus )
• Central service project - Analysis and Synthesis of sphingolipids (Applicant Kleuser, Burkhard )
• Ceramide kinase and its contribution to inflammatory and proliferative kidney diseases (Applicants Huwiler, Andrea ;  Pfeilschifter, Josef M. )
• Coordination project: Sphingolipids - Signals and Disease (Applicant Gulbins, Erich )
• Dual role of plasma secreted sphingomyelinase activity during sepsis and development of organ failure (Applicant Claus, Ph.D., Ralf )
• Functional interactions between the activated coagulation factor-X (FXa) and sphingosine-1-phosphate in vascular smooth muscle cells (Applicant Rauch, Bernhard Hermann )
• Induction of plasma membrane ceramides in T cells and their role in functional paralysis (Applicant Schneider-Schaulies, Sibylle )
• Modulation of innate and adaptive immunity by sphingosylphosphorylcholine (Applicant Gräler, Ph.D., Markus )
• Novel inhibitors of neutral and acid ceramidases and their application in experimental therapies of inflammatory and proliferative kidney diseases (Applicant Arenz, Christoph )
• Regulation of pulmonary inflammation in cystic fibrosis by ceramide (Applicant Gulbins, Erich )
• Regulation of vascular permeability by sphingolipids (Applicants Kübler, Wolfgang ;  Uhlig, Stefan )
• Role of sphingosine kinase and sphingolipids in phagosome biology relevant for pathogenic mycobacteria infection in macrophages (Applicant Griffiths, Ph.D., Gareth )
• Role of the Alzheimer's Disease Enzymes and Proteins in Sphingolipid and Glycosphingolipid Homeostasis (Applicant Hartmann, Tobias )
• Roles of endosomal lipid sorting in membrane degradation (Applicant Sandhoff, Konrad )
• Sphingosine-1-phosphate and Alzheimer's disease (Applicants van Echten-Deckert, Ph.D., Gerhild ;  Walter, Ph.D., Jochen )
• Sphingosine-1-Phosphate Receptors in Human B Cells: Expression, Role and Signaling (Applicant Eibel, Hermann )
• Sphingosylphosphorylcholine and its contribution to pathophysiological processes in the kidney (Applicant Pfeilschifter, Josef M. )
• Subcellular characterization and modulation of sphingolipid-metabolizing enzymes as key regulators of dendritic cell differentiation and their immune deviating function (Applicant Radeke, Heinfried H. )
• The acid sphingomyelinase/ceramide hypothesis of major depression (Applicants Gulbins, Erich ;  Kornhuber, Johannes )
• The relevance of sphingolipids in inflammatory cardiovascular disease: Signaling of S1P1 and S1P3 receptors (Applicants van der Giet, Markus ;  Kleuser, Burkhard )
• The role of HDL-bound and unbound S1P in human and mouse atherosclerosis (Applicant Levkau, Bodo )
• Topology, regulation and function of acid sphingomyelinase in death receptor signaling (Applicant Schütze, Stefan )

• Spokesperson: Professor Dr. Erich Gulbins