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This new program project is focused on the genetics and biology of von Willebrand factor (VWF) and von Willebrand disease (VWD). With a sophisticated MultiOmics approach, the program will address the genetics and genomics of low VWF, the determinants of higher VWF in individuals of African Ancestry, the effects of aging in VWF levels and bleeding symptoms, and determine the molecular causes of VWD that lie outside of the coding sequence for VWF. By studying the life cycle of VWF and its intimate relationship with Factor VIII, with a combination of cellular and animal models, the program will also address the molecular mechanisms that determine VWF expression in different endothelial cell beds, its role on protection of Factor VIII from the unfolded protein response and the impact of glycosylation on expression and trafficking. Finally we will also study the impact of VWF glycobiology on clearance pathways and inflammation, and the immunomodulatory role of VWF. These proposed synergistic and complementary studies will shed light on the pathophysiology of the most common inherited bleeding disorder.

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