During my research project we mainly focussed on studying the pathophysiology of venous and arterial thrombosis in mice. When we transiently lowered plasma protein levels of natural anticoagulants... Show moreDuring my research project we mainly focussed on studying the pathophysiology of venous and arterial thrombosis in mice. When we transiently lowered plasma protein levels of natural anticoagulants antithrombin and protein C using RNA interference, mice developed venous thrombosis in the head. In contrast to other mouse models for venous thrombosis where surgery is required for provoking the disease, mice injected with RNA interference against the mRNA of Serpinc1 and Proc (antithrombin and protein C, respectively) developed venous thrombosis without additional handlings. In this unique form of venous thrombosis, we studied the roles of platelets, neutrophils, and coagulation factor XII. These factors have been shown to be indispensable in experimental venous thrombosis in other mouse models, and they have been introduced as novel therapeutic targets. For the second part of my thesis we again used the RNA interference approach, to lower natural anticoagulation in atherosclerotic mice. When we lowered protein C in these mice, they developed atherothrombosis in the aortic root without any additional intervention. This unique form of atherothrombosis has been showed in multiple independent experiments, and we aimed to further characterize the process to learn more about prevention atherothrombosis in atherosclerotic mice and the role of protein C. Show less
Adverse drug reactions are problematic for both society and pharmaceutical industry. The costs are high in severe cases: for pharmaceutical companies due to the loss of income if a drug needs to be... Show moreAdverse drug reactions are problematic for both society and pharmaceutical industry. The costs are high in severe cases: for pharmaceutical companies due to the loss of income if a drug needs to be removed from the market; for society due to the extra healthcare that is required to treat the affected individuals. Liver damage upon drug intake is the most common type of adverse drug reaction and reason for drug withdrawal. What makes the liver such a vulnerable target is its role as the main drug-metabolizing organ and its large amount of stationary immune cells. This results in frequent exposure to drug metabolite-induced and inflammatory stress. In this thesis I have investigated the role of the signaling induced by the pro-inflammatory cytokine TNF_ in the exacerbation of drug-induced liver injury using an in vitro liver cell model. Using this model and methods such as high content imaging, gene array analysis and functional genomics we have gotten closer to understanding the molecular mechanisms of liver injury. This knowledge can be used to design novel tests for the drug-industry to assess the toxicity of novel drug candidates as well as to pin-point potentially susceptible individuals. Show less
