Role of Class I PI3 kinase in platelet-leukocyte interactions, innate immunity and deep vein thrombosis

Supervisors: Dr Hers, University of Bristol and Prof O’Donnell, Cardiff University.

Deep vein thrombosis (DVT) is a potentially life threatening condition characterised by the formation of an occlusive clot in the intravascular veins that can detach and lead to a pulmonary embolus. Platelets have a known role in thrombosis and haemostasis but also contribute to innate immunity by binding to and releasing factors, including eicosanoids, lipids and DAMPs, that activate leukocytes. In turn activated leukocytes express tissue factor, linking activation to coagulation, and release numerous factors that affect various aspects of platelet function and thrombus formation. Recent studies showed that platelet-leucocyte interactions are major contributing factors to deep vein thrombosis, where sterile activation of the innate immune system underlies thrombus formation, formation of neutrophil extracellular traps (NETs), activation of the coagulation system and fibrin formation.

We and others have previously shown that the Class I family of PI3 kinases is involved in platelet hyperactivity and enhanced thrombus formation, as well as increasing platelet function downstream of P2Y12, an established anti-platelet drug target. PI3 kinase not only directly affects platelet function, but also feeds into the PLA2/COX pathway, thereby stimulating release of eicosanoids and various lipids that in turn can activate leucocytes, stimulate NETs formation and DTV. Although generic PI3kinase inhibitors inhibit platelet-leucocyte interactions, the underlying mechanism by which Class I PI3 kinase regulates platelet-leucocyte interactions and contributes to deep vein thrombosis is still largely unknown.

In this study, we therefore aim to explore the role of Class I PI3 kinase in platelet-leucocyte interactions, activation of the innate immune response/NETs formation and its contribution to deep vein thrombosis in in vivo mouse models. We will focus on the role of different Class I isoforms in platelets and leucocytes by targeting individual Class I isoforms both pharmacologically (isoform selective inhibitors) in human and mouse platelets as well as genetically (conditional Class I isoform specific knock out mice). This is a novel and important area of research that will further elucidate cross-talk between platelets and innate immunity, and although challenging, has high feasibility in generating results within the PhD period.

Together, this project will be an exciting collaboration between the University of Bristol (Dr Ingeborg Hers) and the University of Cardiff (Prof Valerie O’Donnell), and combine a range of different approaches and disciplines, including functional cell biology, cell signalling/biochemistry, imaging, mass spec lipodomics, computational analysis and in vivo mouse models to elucidate the role and underlying mechanism by which Class I PI3kinases contribute to platelet-leucocyte cross-talk and deep vein thrombosis.