B03 - Cell type-specific expression of sphingosine kinase-1, -2, and S1P lyase and its role for inflammatory bowel disease and colon cancerogenesis
Dendritic cell(DC)-derived signals are prominent determinants of the immune pathology of chronic inflammatory bowel diseases (CED), like Crohn’s disease (IL-12/Th1), ulcerative colitis (IL-33/IL-13/Th2), and moreover of colon cancerogenesis (IL-23/IL-6/STAT3). The investigations proposed herein aim to determine the modulatory effect of sphingolipid enzymes (SphLE: SphK1, SphK2 and S1P lyase) on intracellular DC signalling cascades in vitro, as well as in vivo in murine models of CED and colitis/colon cancer. The experimental tools employed include SphLE-deficient mice, DC-optimised, conditional lentiviralshRNA vectors and SphLE-specific inhibitors and are complemented by intravital mouse coloscopy. To define the pathologic role of cellular immune infiltrates versus local colon epithelia we will generate bone-marrow chimeras for the respective SphLE. With these studies we expect to unravel the contribution of SphLE to CED pathophysiology and colon cancerogenesis and to identify their potential as therapeutic targets.
Prof. Dr. Heinfried H Radeke
Institute of General Pharmacology and Toxicology
Faculty of Medicine
Theodor Stern Kai 7
60590 Frankfurt am Main