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GRK 2098:  Biomedicine of the acid sphingomyelinase/acid ceramidase system

Subject Area Medicine
Term from 2015 to 2020
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 259317790
 
Final Report Year 2020

Final Report Abstract

The present Graduiertenkolleg/Research Training Grant (GRK 2098/RTG 2098) focused on the biomedicine of sphingolipids. Sphingolipids are central to many fundamental cellular processes such as proliferation, differentiation and cell death, but also play an important role in bacterial and viral infections, cystic fibrosis, pneumonia, multiple sclerosis, cardiovascular diseases, cancer, major depression, neuro-degenerative diseases, or macular degeneration to name a few examples. The RTG 2098 focused on the role of sphingolipids in infectious biology, immunology, autoimmune syndroms, cancer and cardiovascular diseases. The projects focused strictly on the acid sphingomyelinase/ceramide/acid ceramidase/sphingosine/ sphingosine kinase/sphingosine 1-phosphate (S1P) pathway. The RTG provided training for PhD, MD/PhD, MD, and high school students in these emerging fields of the biomedicine of sphingolipids. One of the highlights of the RTG 2098 demonstrated a novel function of sphingosine as anti-viral defense mechanism in multivesicular bodies targeting viruses to lysosomal degradation. These studies describing a novel and principle role of sphingolipids in infectious biology were published in Nature Communications. A second highlight is the finding that expression of the acid sphingomyelinase is part of the defense against Citrobacter rodentium and that deficiency of the acid sphingomyelinase results in an overwhelming infection and an uncontrolled inflammatory Th1 and Th17 response, collectively triggering severe colitis. The studies were published in Front. Immunol. In line with a protective role of the acid sphingomyelinase in infections are the findings that a Tlymphocytes-specific overexpression of the acid sphingomyelinase reduced parasitemia during Plasmodium yoelii infection. The studies were also published in Front. Immunol. Further studies on the role of the acid sphingomyelinase in the immune system revealed that this enyzme controls activation and proliferation of CD4 T cells and the number of regulatory T cells in vivo. In accordance with increased numbers of immunosuppressive regulatory T cells in acid sphingomyelinase-deficient mice, members of the RTG 2098 showed that inhibition of the acid sphingomyelinase prevented the development of an auto-immune arthritis. These findings are consistent with a downregulation of an overshooting immune response upon inhibition of the acid sphingomyelinase. On the other hand, consumption of ceramide to sphingosine 1-phosphate was shown by studies within the RTG 2098 to promote influx of pro-inflammatory immune cells into the orbita in Graves' Orbitopathy. These studies were published in Thyroid and Invest. Ophthalmol. Vis. Sci. Collectively, the studies demonstrate that the balance between ceramide, sphingosine and sphingosine 1-phosphate plays an important role in the response of the immune system to bacteria, viruses and parasites. Another highlight of the RTG 2098 identified a novel role of sphingolipids in vasculogenesis after stroke and demonstrated that functional inhibitors of the acid sphingomyelinase promote vasculogenesis after ischemic stroke. Additional studies within the RTG 2098 demonstrated a role of the acid sphingomyelinase in tumor metastasis, in activation of macrophages upon infection with mycobacteria and the pathogenicity of toxins. Basic studies investigated the role of sphingosine 1-phosphate and its receptors in the development of aortic aneurysms, cholesterol efflux and cholesterol trafficking. The teaching program of the RTG focused on a specific and extensive training in sphingolipid biology and biomedicine. We offered the students a great variety of teaching instruments includingregular presentations, seminars, research days, discussion of the thesis, participation on many scientific meetings and research stays in partner laboratories in New York.

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