Grant: Operating Grant

The protein von Willebrand factor (VWF) plays a number of roles in facilitating the clotting of blood. von Willebrand factor acts as the molecular bridge between the damaged blood vessel wall and circulating platelets, and also carries one of the clotting factors, factor VIII, in the blood. Finally, under some circumstances, VWF also contributes to the stabilization of platelets at the site of vessel injury. An inherited deficiency or dysfunction of VWF results in a bleeding disorder, known as von Willebrand disease (VWD). In contrast, high levels of VWF in the blood or the presence of VWF with enhanced functional capacity is associated with a greater risk of abnormal clotting (thrombosis). The aim of the studies described in this proposal is to elucidate new information concerning three distinct features of VWF structure and function. In the first series of experiments, we will examine the potential role for the secreted propeptide sequence of VWF. Why the propeptide is secreted, whether it has an extracellular function and where it is cleared from the blood are all unknown and will be the focus of studies in this project. The second group of studies will address the role of VWF as a carrier of FVIII. In these experiments, we will generate several mutant forms of VWF known to result in reduced binding and stabilization of FVIII, so called type 2N VWD variants. These proteins will be studied in a range of in vitro and in vivo experimental systems to determine their influence on a variety of hemostatic functions. Most importantly, we will determine the importance of VWF transporting FVIII to the site of vascular injury. In the final group of experiments, we will focus on a potential novel clearance mechanism for VWF. These studies will examine a scavenger receptor, SCARA5, recently identified in genetic studies as a candidate VWF clearance receptor. We will incorporate biochemical, cell biology and animal model approaches to address this final research aim.