FOR 1543:  Shear Flow Regulation of Hemostasis - Bridging the Gap between Nanomechanics and Clinical Presentation

• Subject Area: Biology ; Medicine
• Term: from 2011 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 172540668

Taking the next step - Origin and Role of Collective Processes Controlled by VWF and Shear FlowFocus of our research is the von Willebrand factor (VWF) a key player in primary hemostasis, FVIII clearance and, as demonstrated by SHENC members and others recently, pivotal during inflammation and tumor metastasis. SHENC´s unique and challenging combination of medical and physiological expertise, experimental and theoretical (molecular) biophysics and nanotechnology established during the first funding period has been proven extremely successful and is reflected in multiple interdisciplinary publications (see 4.1). We significantly advanced the understanding of the molecular basis of activation, adhesion and degradation of single VWF molecules, developed key methodologies in the field, which foster the design of new diagnostic tools, and we were able to relate genetic variations of VWF to novel shear-dependent dysfunctions. As a result our research unit has bundled its strength and has paved the way to take the next step in bridging the gap between VWF´s molecular properties and clinical presentation. The goal of the next funding period is to extend our view on VWF in at least two fundamental directions (Figure 1):1) Physical origin and (patho)physiological role of dynamic collective networks: Under whole-blood-like conditions nearly macroscopic networks of VWF and platelets form reversibly when subjected to increasing shear flow. The clinical role as well as the physical and molecular origin for the formation of these dynamic collective networks is a mystery, although their existence in vivo was recently proven by SHENC group A2 in ex vivo tissue sections obtained from patients. We provide the critical mass to bridge the gap between the occurrence of these networks and the clinical presentation resulting from alterations in their formation.2) Role of VWF during inflammation: Platelet and leucocyte adhesion, endothelial permeability and surface properties, VWF degradation by ADAMTS13 as well as likelihood of thromboembolic events are significantly altered during inflammation. The role of VWF in all these processes remains unclear and will be unraveled using the combined power of our research unit. A new generation of in-vitro-model-systems will be designed and will be combined with theoretical studies and computer simulations.In summary, the formation of collective networks under dynamic and inflammatory conditions has to be expected to be critical for thrombus formation, vascular occlusions, myocardial infarction and stroke. A fundamental understanding of their formation will therefore open new avenues to diagnose, intervene and treat such devastating events.

• DFG Programme: Research Units
• International Connection: Austria, USA

Projects

• Binding and conformational changes of VWF under shear (Applicant Rädler, Joachim )
• From Single Molecules to Collective Phenomena - The Origin of VWF-Induced Collective Networks (Applicant Wixforth, Achim )
• Interrogation of structure-function relationships in network formation of von Willebrand Factor domains by X-ray crystallography (Applicant Wilmanns, Ph.D., Matthias )
• Mechanical properties of VWF in single molecule and cell adhesion force experiments using AFM (Applicant Benoit, Martin )
• Modeling the flow behavior of blood cells and von Willebrand factor in primary hemostasis (Applicant Gompper, Gerhard )
• Pathophysiology of von Willebrand factor in the circulation (Applicant Schneppenheim, Reinhard )
• Polymer models for sheared VWF at surfaces (Applicant Netz, Roland )
• Structural investigations of VWF under flow by FTIR spectroscopy (Applicant Gerwert, Klaus )
• The molecular basis of VWF mechano-sensoring: Structure and interactions of VWF domains as the basis for regulation and aggregation (Applicant Gräter, Frauke )
• Von Willebrand factor under inflammatory conditions - Von Willebrand factor-induced collective networks (Applicant Schneider, Stefan Werner )
• Zentralprojekt (Applicant Schneppenheim, Reinhard )

• Spokesperson: Professor Dr. Reinhard Schneppenheim
• Deputy: Professorin Dr. Frauke Gräter