Omega-3 Poly Unsaturated Fatty Acids (PUFA’s) are present in fatty fish (like tuna, mackerel and salmon) and fish oil supplements, which is the primary source of these molecules for humans. In humans, PUFA’s are easily transferred to endocannabinoids, which are amide derivatives of PUFA’s. Endocannabinoids have potent anti-inflammatory behaviour and have shown to inhibit various chronic inflammatory diseases like arthritis, cardiovascular diseases and even cancer and obesity. An important endocannabinoid that showed anti-inflammatory effects is docosahexaenoyl ethanolamide (DHEA). Important for the anti-inflammatory response of DHEA is the role cyclooxygenase-2 (COX-2). Nevertheless, it is uncertain what the exact role of DHEA on COX-2 is. Our final goal then is to elucidate the modulation of inflammation by DHEA.
In this project various DHEA derived probes will be synthesized to specifically ‘fish’ for new receptors and proteins that are involved in the endogenous anti-inflammatory response of inflamed cells. Various bio-orthogonal handles are being introduced in the ‘head’ and ‘tail’ part of the endocannabinoid structure. These self-synthesized endocannabinoid probes are used to study the exact role of COX-2. Secondly, the probes are used for activity based proteomics and in-vivo imaging. In this way new receptors and regulator proteins can be discovered that regulate the anti-inflammatory response of the endocannabinoids or their possible COX-2 derived metabolites. This project thus uniquely combines the chemical synthesis of endocannabinoid probes, and biological studies to investigate the metabolic fate of the endocannabinoid probes and the underlying anti-inflammatory mechanism.