The research conducted in my laboratory focuses on understanding how cells regulate blood clotting in health and disease. The blood clotting system is activated when an enzyme (a specific plasma serine protease known as factor VIIa) binds to a particular integral membrane protein (known as tissue factor, or TF) on cell surfaces. The TF-VIIa-membrane complex triggers the blood clotting cascade by activating two plasma serine protease zymogens (factor IX and factor X) via limited proteolysis.
Thrombosis is the formation of unwanted blood clots inside arteries and veins, which represents the leading cause of disability and death in the world. Tissue factor is the protein that triggers thrombosis in many–possibly most–disease settings. For this reason, it is critically important to understand how the initiation of coagulation is controlled via tissue factor and factor VIIa.
We are currently focusing on the following research questions:
- How do the serine proteases of the blood clotting system assemble together with specific regulatory proteins on cell surfaces and other membrane surfaces?
- Why are membranes required for efficient proteolysis by these enzymes? What role do specific phospholipid types play in modulating the activity of blood clotting proteases?
- We recently discovered that inorganic polyphosphate secreted from activated platelets is a potent modulator of blood clotting and fibrinolysis. What’s the mechanism by which polyphosphate does this?
- As a spinoff from this basic research, we are also working to develop:
- Improved diagnostic tests for identifying persons at risk of thrombotic disease.
- Improved hemostatic agents to treat bleeding, including traumatic and surgical bleeding.