Blood Proteins & Engineering
In our research program, the combination of recombinant protein expression, total chemical protein synthesis and protein homology modeling is applied to the field of protein engineering and structure-function relationships of coagulation factors. In addition we apply molecular biology, DNA analysis (genomics), and epidemiology to the analysis of plasma samples from patients that have experienced thrombosis to analyze the impact of impaired anticoagulant pathways on the overall prothrombotic response in plasma. The calibrated automated thrombin generation (CAT) assay, that has currently found its applications world wide, was developed within our program. The activated protein C(APC)-resistance assay that is based on the CAT assay is used as a validated marker of thrombotic risk (e.g. due touse of oral contraceptives, hereditary risk factors) and for monitoring anticoagulant therapy of any type. Using this assay, major contributions have been made to unravel mechanisms of anticoagulant pathways and to understanding prothrombotic responses as a result of their impairment. In addition, with the use of CAT assays, the tissue factor pathway inhibitor (TFPI)-cofactor activity of protein S was uncovered, defining a new virtually unexplored research area. Total chemical synthesis of proteins is applied to the molecular targeting and imaging of thrombosis. Solid phase peptide synthesis and native chemical ligation enable total chemical synthesis of functional domains and complete proteins with correct three-dimensional structure that allow single and specific labeling of proteins and peptides with fluorescent or MRI/ SPECT/PET tags that are successfully applied to the imaging of thrombotic processes in vivo.