Project Details
Projekt
Von Willebrand factor under inflammatory conditions - Von Willebrand factor-induced collective networks
Applicant
Professor Dr. Stefan Werner Schneider
Subject Area
Hematology, Oncology
Biophysics
Biophysics
Term
from 2011 to 2015
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 172540668
The active role of endothelium is one of the key factors for the initial step of inflammation. Endothelial cell (EC) activation leads to an immediate release of various proteins, cytokines and the adhesive glycoprotein von Willebrand factor (VWF). Exposed to the blood flow, VWF shows a state-function-relationship: the glycoprotein multimers become stretched and form fibre-like structures immobilised on EC surface. As a consequence of the critical coiled-stretched transition and subsequent binding, VWF is a shear-activated protein and thereby uncovers formerly shielded binding sites. Hereafter, the regular repressive function on inflammation and coagulation subsides and the endothelium converts to a proinflammatory and procoagulatory surface. VWF can be therefore also considered as a shear-dependent inflammatory molecule bridging coagulation and inflammation.Within the last funding period we elucidate the formation of EC-secreted VWF and the impact of large VWF multimers on platelet/leukocyte/bacteria adhesion under defined shear rates upon inflammatory conditions. Therefore we addressed the role of shear flow conditions for the activation and self-assembly of endothelium-derived VWF and the impact of an inflammatory milieu on the activity of VWF and its degrading protease ADAMTS13. Our objectives for the requested funding period arise from the combined effort of all SHENC groups to elucidate the sheardependent functions of VWF, illustrated by numerous project-related multidisciplinary publications. The recent insights into the process of self-assembly of VWF, resulting in its ability to induce collective network formation under high-shear conditions, represent an auspicious research area of potential high medical impact. So far unexplored, the characteristics of this collective network formation, defined by the state of VWF in the micromilieu of inflammatory conditions, will be our key target for the requested funding period. Therefore, our research will concentrate on the following main aspects:Focusing on VWF-induced collective networks we want to uncover the mechanistic, functional and pathophysiological background of their formation, activation and degradation. Our established in vitro vascular model system allows a capacious characterisation of the shear-induced activation capacity and collective network behaviour of VWF and distinct VWF mutations. Clinical relevant VWF mutations, so far failed to be functionally diagnosed by standard assays, will be reliably identified and mechanistically analysed. Furthermore, we will broaden our methodological spectrum by implementation of electrical cell-substrate impedance sensing, thereby addressing the role of VWF on its reflexive effect on EC function and vascular permeability under flow conditions. Moreover, the impact of shear-activated VWF on leukocyte trafficking via the mediator extracellular DNA will be of high interest for further investigation.
DFG Programme
Research Units
