Role of Monocyte and Endothelial Cell Tissue Factor and PAR-1 in Sepsis

Current estimates indicate that each year more than 700,000 new cases of sepsis occur in the United States and it is one of the leading causes of death in the western world. Sepsis is caused by the presence of pathogens in the blood and the unregulated over-reaction of the host immune system. Sepsis is often associated with systemic activation of blood coagulation and subsequent multiorgan failure and death. The broad goal of this project is to elucidate the role of the coagulation protease cascade and protease activated receptor signalling by both myeloid and non-myeloid cells in sepsis. In detail we will investigate the role of monocyte and endothelial tissue factor (TF), which is the primary cellular initiator of blood coagulation, and protease activated receptor 1 (PAR-1), which is the major thrombin receptor. We will employ bone marrow transplantation and genetically modified mice to understand how TF and PAR-1 expression on different cell types contributes to sepsis.