The Von Willebrand Factor-Macrophage Intracellular Signaling Study (VWF-MISS) in linking hemostasis and inflammation

Von Willebrand factor (VWF) is a large multimeric glycoprotein that circulates in plasma and plays a key role in primary hemostasis at sites of vascular injury. In addition, recent studies have highlighted a novel role for VWF in regulating inflammation in multiple human pathologies, including cardiovascular disease, von Willebrand disease, and several cancers. Notwithstanding these findings, the biological mechanisms through which VWF exerts its immunomodulatory effects remain poorly understood. The overarching aim of the VWF-Macrophage Intracellular Signalling Study (VWF-MISS) is to gain novel insights into the molecular mechanisms through which VWF regulates macrophage biology over the course of an 18-month fellowship. Specifically, VWF-MISS will characterize i) the macrophage receptors involved in modulating the pro-inflammatory response, ii) the molecular basis involved in the temporal regulation of VWF signalling, and iii) the role of specific VWF domains and/or mutations in regulating macrophage inflammatory signalling using a wide range of in vitro laboratory strategies and bioinformatics (RNA-sequencing). As such, the applicant will integrate existing expertise from the Royal College of Surgeons in Ireland O’Donnell laboratory (VWF biology; host organisation) and Trinity College Dublin Fallon laboratory (innate immunity; secondment) to address these research objectives. The concept that VWF plays a key role at the interplay of hemostasis and inflammation has clear translational relevance with respect to both bleeding and thrombosis and presents the intriguing possibility that specific targeting of the VWF-macrophage interaction could offer exciting therapeutic opportunities. The VWF-MISS project will equip the applicant with transferable laboratory and analytical skills, that, combined with her clinical background, will significantly advance her career goal to direct a scientific research program relating to the crosstalk between hemostasis and immunity.