Deciphering the role and regulation of lipid mediators in health and disease

Lipid mediators are derived from fatty acids and include the prostaglandins (PG) and leukotrienes (LT), which are involved in a range of physiological and pathogenic processes such as fever, pain, arthritis, asthma and cardiovascular diseases. This project is focused on deciphering the roles and regulations of these potent autocoids.

Here, we will characterize nexus enzymes in the PG/LT pathways, including soluble 5-LO and LTA4H as well as integral membrane proteins, denoted MAPEG, required for both LT and PG synthesis.We will solve structures, use biorthogonal labeling of enzymes in HEK cells and MD simulations to elucidate structural dynamics associated with enzyme traffic, membrane association and catalysis, and dissect their assembly in enzyme complexes at the nuclear membrane.

Further, we will explore the interface between lipid mediators and “metabolism” with focus on metabolite GPCRs in mast cells, involved in allergic inflammation.

New and existing enzyme inhibitors will be tested in cellular and in vivo disease models to dissect the role of specific mediators and identify new therapeutic applications.

The project is multidisciplinary and is conducted within the framework of international collaborations and national infrastructures.

Our project will provide new molecular knowledge about medically important proteins and, with time, has the potential to generate novel strategies for prevention and treatment of serious endemic and disabling diseases.