John Parker Professor of Medicine
- Role of Tissue Factor in hemostasis, thrombosis and ischemia-reperfusion (I/R) injury
My lab studies the gene expression in human monocytes, focusing on tissue factor (TF), which is the primary cellular initiator of blood coagulation, and the proinflammatory cytokine TNFα.
We have elucidated the role of different intracellular signaling pathways in the induction of the TF and TNFα genes in monocytes. These pathways include the mitogen activated protein kinases (MAPK) ERK1/2, p38 and JNK1/2. In addition, my lab has studied the I kappa kinase that phosphorylates the IκB inhibitor proteins leading to their degradation and release of NFκB proteins into the nucleus. More recently, we have investigated the inhibition of the MAPK pathways by the PI3K-Akt pathway and also by antioxidant compounds.
In parallel to the in vitro studies, my lab has established several animal models of various diseases to analyze prothrombotic and proinflammatory responses in vivo. These include the endotoxemia model and a renal ischemia/reperfusion (I/R) injury model. We are interested determining the mechanism of crosstalk between coagulation and inflammation in these models. We have focused on the protease activated receptor (PAR) family because these proteins are activated by coagulation proteases.
Gram-negative bacterial infections release LPS that activates monocytes of the innate immune system. These cells express various inflammatory mediations, including cytokines and procoagulant molecules, to combat the infection. However, over-reaction to LPS can lead to septic shock. We are studying the signaling pathways and other mechanisms by which anti-inflammatory mediators and anticoagulants reduce the inflammatory response to LPS during sepsis.
I/R injury is a significant clinical problem that contributes to morbidity and mortality. We showed that inhibition of either TF or the downstream coagulation protease, thrombin, reduces infarct size in a rabbit model of myocardial I/R injury. Furthermore, we determined that the TF-thrombin pathway contributed to the inflammatory response during myocardial I/R injury by increasing chemokine expression and recruitment of neutrophils. More recently, we found that activation of the major thrombin receptor, called PAR-1, contributed to cardiac remodeling after I/R injury. We have written a patent proposing that inhibition of PAR-1 represents a novel therapeutic approach to treat cardiac hypertrophy and heart failure.
The lab also studies the role of TF in tumor growth and tumor angiogenesis. In collaborative studies with Janusz Rak in Toronto, we have demonstrated that TF expression in human colorectal cancer cells was regulated by activation of the K-ras oncogene and inactivation of the p53 tumor suppressor. In addition, a selective reduction in TF expression in cancer cells was associated with reduced growth and reduced angiogenesis when the cells were injected into mice. We have also demonstrated that cancer patients have elevated levels of circulating TF, which may contribute to the increased incidence of thrombosis in these patients.
Finally, my lab has generated a number of mouse models expressing different levels of TF. These mice have been used to provide new insights into the role of TF in both hemostasis and thrombosis. We have proposed a model of tissue-specific hemostasis. In the future, the lab will continue to study the role of the clotting cascade and platelets in hemostasis, thrombosis and inflammation. I hope to discover new treatment for hemostatic and thrombotic diseases.