Tissue factor (TF) is a transmembrane protein that functions as a high-affinity receptor for factor (F)VII and FVIIa. The TF-FVIIa complex is the primary initiator of coagulation and plays an essential role in hemostasis. However, aberrant TF expression underlies most forms of thrombosis. TF expression is also induced in response to bacterial and viral infections as part of the innate immune response. This expression can be either protective by limiting the spread of the pathogen or pathologic by triggering disseminated intravascular coagulation (DIC). TF-dependent generation of coagulation proteases also leads to activation of protease-activated receptors (PARs). My lab has made major contributions to understanding the roles of TF, coagulation proteases and PARs in hemostasis, thrombosis, endotoxemia, ischemia-reperfusion injury, atherosclerosis, and viral infections. This R35 OIA application is an extension of two NHLBI funded R01 grants: Mechanism of venous thrombosis in pancreatic cancer; Role of the thrombin PAR1 pathway in viral infection. We have shown that levels of circulating tumor-derived, TF+ extracellular vesicles (EVs) are associated with increased venous thromboembolism in pancreatic cancer patients. In addition, we found that TF+ EVs enhance venous thrombosis in mice bearing human pancreatic tumors. We have also shown that TF-dependent activation of coagulation and PAR1 signaling is protective in response to Coxsackievirus B3 by boosting the antiviral IFN? pathway in the heart. In contrast, PAR1 suppresses the pathologic NF-?B response in the lung in response to influenza A H1N1 infection. The OIA funding mechanism would provide stable funding and increased time for our group to pursue higher risk-higher reward projects, such as performing proteomic analysis of plasma and EVs, establish new technologies, such as the ExoView system, and following up on exciting discoveries. Our long-term goals are to further understand the protective and pathologic roles of TF, coagulation proteases and PARs in cancer and infections. There are two hypotheses for this proposal: 1/ TF enhances venous thrombosis and tumor growth in pancreatic cancer, and 2/ TF-dependent activation of coagulation is both protective and pathologic in response to viral infection. We will continue our studies on the identification of plasma biomarkers of thrombotic risk in cancer patients using clinical samples. We will identify prothrombotic pathways that contribute to cancer- associated thrombosis using mouse models. In addition, we will determine the roles of tumor and host derived TF in the growth of pancreatic tumors in mice. We will identify the cellular sources of pathologic TF in mouse models of viral infection that may lead to new treatments to prevent DIC. We will elucidate how PAR1 is protective by both enhancing the IFN? antiviral pathway in the heart and suppressing the pathologic NF-?B pathway in the lung in response to viral infection. This knowledge may lead to the identification of new biomarkers of thrombotic risk, treatments for pancreatic cancer and protection from viral infection.
This project will investigate the role of tissue factor (TF) and TF-dependent signaling in venous thrombosis and growth of human pancreatic cancer, as well as its contribution to antiviral innate immune responses. We will use a novel mouse model of human pancreatic cancer. In addition, we will improve the current assays to measure extracellular vesicle TF and will identify risk markers for thrombosis in plasma. Furthermore, we will use two well described infection models with Coxsackievirus B3 myocarditis and H1N1 influenza A pneumonia. Our long-term goals are to further understand the protective and pathologic roles of TF, coagulation proteases and PARs in cancer and infections. Our studies might lead to new therapies to improve human health.
