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Regulation of Liver Coagulation Gene Expression

To goal of this research line is to understand the biological mechanisms underlying changes in the hemostatic balance during endocrine and metabolic perturbations, and their relationship to the increased risk of thrombosis. Using recombinant in vivo model systems that express disease phenotypes (obesity, spontaneous thrombosis) or that lack genes key to the mechanistic pathways of interest, studies are on estrogens, progestagens, pregnancy, obesity and thyroid hormone in relation to coagulation and thrombosis. Several relevant technologies were successfully introduced including analysis of  hepatic and vascular coagulation gene expression,  experimental and spontaneous thrombosis. The experimental in vivo research on estrogens (part of Netherlands Heart Foundation grant NHS2006B045) was expanded and integrated with a human approach to study the genetic variations in genes from the estrogen metabolic and response pathways and their contribution oral contraceptive related thrombosis. This work is funded by an ZonMw NWO-TOP Grant (with Dr. A.van Hylckama Vlieg and Dr. F.R. Rosendaal, Clinical Epidemiology, LUMC). As part of the NWO-TOP grant we developed an in vivo RNA interference strategy that allows simple and fast knockdown of hepatically expressed genes with minimal target- and methodology- related secondary effects. We successfully validated this strategy for a number of genes (potentially) relevant to coagulation with 75-85% hepatic knockdown for at least 5 days after administration of lipid-complexed synthetic siRNA). In collaboration with Prof.Dr. Frank. J. Gonzalez (National Institutes of Health, Bethesda) and Dr. Yusuke Inoue (Gunma University Kiryu, Japan) we used this in vivo siRNA approach to evaluate the direct role of HNF4α in coagulation gene transcription. Very recently, the siRNA approach also allowed us to generate an in vivo model featuring an acute and spontaneous thrombotic phenotype.