Regulation of vascular permeability by sphingolipids

• Antragsteller: Professor Dr. Wolfgang Kübler; Professor Dr. Stefan Uhlig
• Fachliche Zuordnung: Anatomie und Physiologie
• Förderung: Förderung von 2007 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 39051989

The pro-inflammatory mediator platelet-activating factor (PAF) causes pulmonary edema by increasing vascular permeability mediated by acid sphingomyelinase (ASM) and cyclooxygenase. In the current funding period we have shown that the ASM mediates recruitment of caveolin-1, eNOS (endothelial NO synthase) and TRPC6- channels to caveolae which leads to a reduction in endothelial NO synthesis in combination with an increase in cytosolic calcium. These findings indicate that PAF causes edema by simultaneously decreasing NO and increasing calcium levels in the endothelium by ASM-dependent mechanisms. While these ongoing studies have identified the signalling steps by which ASM increases vascular permeability in the lungs, we now aim at A) analyzing these mechanisms in greater detail and B) examining the steps that lead to activation of ASM in response to PAF in the first place. Most of these studies will be performed in intact isolated and perfused rat or mouse lungs. A) To further characterize the PAF-induced alterations in caveolae, we will analyze caveolar fractions obtained by gradient density centrifugation for sphingolipids and proteins by mass spectroscopy. In addition, we will address the interaction of prostaglandin E2, which is responsible for the ASM-independent part of PAF-induced edema, with the recruitment or activation of TRP-channels. B) To understand how PAF activates the ASM, we will focus on src kinase, cAMP-dependent signalling and the possible translocation of the ASM from lysosomes. In addition, we will address the role of the mannose-6-phosphate receptor as an anchor for extracellular ASM. These studies will contribute to our understanding of the regulation of vascular permeability in inflammatory disorders of the lung and will help to identify novel pharmacological targets for their treatment.

• DFG-Verfahren: Schwerpunktprogramme
• Teilprojekt zu: SPP 1267: Sphingolipids - Signal and Disease