In our group, research focusses on the establishment of new test systems and new concepts for the development of antirheumatic drugs. For that purpose, various techniques like mammalian cell culture, protein purification and various molecular biology methods are employed to characterize the enzymes involved in inflammatory reactions. We work on the physiology and pharmacology of 5-lipoxygenase, an enzyme which is involved in host defence reactions.
5-Lipoxygenase catalyzes the transformation of arachidonic acid to leukotriene A4. This unstable intermediate can be converted to leukotriene B4 by LTA4-hydrolase or to leukotriene C4 by LTC4-synthase. Leukotrienes are involved in host defence reactions and play an important role in inflammatory diseases like asthma, psoriasis, inflammatory bowel disease and arthritis. The capability to release leukotrienes is restricted to a few cell types. Under pathophysiological conditions, leukotrienes are released from granulocytes, mast cells or macrophages. During hematopoiesis the competence of these cells for leukotriene biosynthesis is upregulated.
In mature cells, 5-lipoxygenase activity is tightly regulated and seems to be under the control of additional cellular components. Thus, the understanding of the regulatory mechanisms of cellular leukotriene biosynthesis provides new concepts for the development of antiinflammatory drugs.
Besides its catalytic acitivity, 5-lipoxygenase was shown to control p53 and ß-catenin activity which suggests that it acts as a protein which controls the expression of genes involved in the regulation of cell proliferation and differentiation. This provides a previously unknown link between inflammation, tissue and cell rrgeneration and cancer. Furthermore, 5-lipoxygenase has been shown to interact with Dicer and is able to modulate miRNA biosynthesis. Current research projects investigate these noncanonical functions of 5-lipoxygenase.
Ongoing research projects:
- Investigation of the signal transduction cascades involved in 5-lipoxygenase activation and cellular localization
- Mechanistic studies on the formation of specialized proresolving lipid mediators (SPM) in leukocytes.
- Investigation of the noncanonical functions of 5-lipoxygenase
- Mechanistic studies of 5-lipoxygenase inhibition by new chemical entities and the modulation of canonical and noncanonical functions of 5-lipoxygenase
Research of the group is supported by grants from the Deutsche Forschungsgemeinschaft within the CRC "Disease-related Signal Transduction by Fatty Acid Derivatives and Sphingolipids" (SFB 1039), the research training group "Resolution of Inflammation" (AVE) and the LOEWE Schwerpunkt "Transient Binding Sites" (TRABITA).