Molecular mechanisms of lipid-regulated transcription involved in cell activation by bacterial components

In this post-genomic era the major challenge within molecular biology is to understand the biological role of individual genes and delineate how genes interact in cells and organisms. The aim of this project is to delineate lipid-mediated intracellular si gnaling mechanisms and transcriptional activation associated with infectious diseases, in particular sepsis. Sepsis caused by Gram negative and Gram positive bacteria is recognized as a common cause of morbidity and mortality, with mortality rates reachin g 20-40%, despite development of new antiobiotics. Until recently it has not been known how bacteria signal to and activate immune cells, but the recent identification of Toll-like receptors (TLRs), recognizing and mediating cellular pathogen-induced resp onses has provided new knowledge of these processes. However, the molecular mechanisms of pathogen-stimulated TLR-mediated responses are largely unknown. Phospholipase A2 (PLA2) enzymes regulate the production of eicosanoids and bioactive lipid-mediators. In proinflammatory activated cells, e.g. in response to bacterial infection, PLA2 releases arachidonic acid, and PLA2 has been implicated during sepsis. Thus, PLA2 enzymes are implicated in pathogen-induced cell activation, but the receptors conveying PLA2-activity are not known. Therefore, the aim of this project is to elucidate signaling mechanisms and the involvement of PLA2 in cellular responses induced by TLRs. Detailed molecular understanding of signal transduction during bacterial infections is critical for development of novel anti-inflammatory drugs.