Kurzfassung

Blood platelets play a key role in the regulation of hemostasis and in the genesis of thrombotic events. Platelets can attach almost instantly to injured vessel wall, subendothelial matrix or other, activated platelets and contribute considerably in development and progression of cardiovascular
diseases. As a result of their central role,in physiological as well as pathological respect, platelets are tightly regulated by numerous factors acting either stimulatory or inhibitory and,...Blood platelets play a key role in the regulation of hemostasis and in the genesis of thrombotic events. Platelets can attach almost instantly to injured vessel wall, subendothelial matrix or other, activated platelets and contribute considerably in development and progression of cardiovascular
diseases. As a result of their central role,in physiological as well as pathological respect, platelets are tightly regulated by numerous factors acting either stimulatory or inhibitory and, occasionally, in both ways. Most of these factors bind to specific receptors thus governing distinct intracellular pathways . A strictly regulated equilibrium of activatory and inhibitory signals is apparently essential for the physiological function of platelets and vessel wall. Two endogenous factors, namely adenosine-diphosphate (ADP) and prostacyclin (PGI2), which play a particular role in physiology and pathophysiology by maintaining the equilibrium of platelet activation and inhibition are in
the focus of this project. Though ADP is regarded a rather weak platelet agonist in recent
years it became evident that a complete platelet aggregation is only possibly by activation of ADP stimulated pathways. The sole inhibition of one of the three ADP receptors known for platelets is sufficient to prevent thrombus formation. PGI2 is clearly the most relevant and efficacious inhibitor
of platelet aggregation. The short lived prostaglandin is formed by the endothelium lining the vessel wall and acts directly on the platelets passing by. As a matter of fact it turned out that PGI2 and ADP are indeed direct opponents in the physiological regulation of platelet function.The SARA research consortium aims at a description of ADP and PGI2 evoked signaling pathways by applying molecular biological, biomedical, biochemical and bioinformaticalmethods with respect to quantity
and time course. In an iterative strategy protein phosphorylation, formation of messenger molecules as well as cellular responses such as secretion or aggregation after stimulation of ADP and/or PGI2 induced pathways are investigated. Protein phosphorylation is determined by innovative techniques allowing for identification of phosphorylation sites – by means of SH2-
profiling – and an absolute quantification of phosphorylation by quantitative phosphoproteomics. The findings are integrated in a bioinformatical model of the signaling cascades which will be further refined by additional more specific analysis. Markers for platelet activation and inhibiiton identified coherently will then be verified in a large group of volunteers. Eventually a meaningfiukl
model of platelet function regulation will be developed which will improve our understanding
of the genesis and development of atherothrombotic diseases. In addition it is expected that the project will provide novel approaches for diagnosis and therapy of atherothrombosis.» weiterlesen» einklappen