Berit Johansen
Norwegian University of Science and Technology, Norway
Title: Cytosolic Phospholipase A2, a powerful regulator of inflammation and a potent candidate for therapeutic intervention in chronic disease
Biography
Biography: Berit Johansen
Abstract
Eicosanoids, the oxygenated metabolites of arachidonic acid (AA) comprise a large family of bioactive lipids that have diverse roles in regulating homeostatic processes, in modulating inflammation and immune responses. Phospholipase A2s (PLA2s) are a group of enzymes that hydrolyze the sn-2 position of membrane phospholipids to release (typically unsaturated) fatty acids, including AA, and lysophospholipids. Three major classes of PLA2s exist in the mammalian system, including low molecular weight extracellular or secretory, sPLA2; high moleular weight calcium-independen, iPLA2; and the group IVA calcium-dependent cytosolic PLA2, cPLA2α. The latter has received the most attention because it is widely expressed in nearly all mammalian cells and due to its active participation in cell metabolism. cPLA2ï¡ is identified as the the rate-limiting provider of proinflammatory mediators, including AA, and is thus an attractive target for the development of novel antiinflammatory agents. It is found that cPLA2α plays a major role in the chronic inflammation characterizing both psoriasis and rheumatoid arthritis. Novel inhibitors showing high potency and selectivity targeting cPLA2α are developed. These represent different chemistries, thus enabling various regimes for formulation, administration and tissue accumulation. Results will be presented to demonstrate mode of action for potent cPLA2α inhibitors in relevant cellular model systems for psoriasis and rheumatoid arthritis, efficacy in animal models of disease and “Proof of concept” for treatment of human disease.