Areas of Interest
Enzymology, Membrane Biology, Protein Structure
Protein-phospholipid interactions; regulation of protease cascades; blood clotting; polyphosphate
A number of important biological processes, including apoptosis, the complement system and blood coagulation, are controlled by protease cascades. A key regulatory feature of such cascades is the modulation of protease function by highly specific protein cofactors, and interestingly, these cascades often can only take place on membrane surfaces. Although much is known about the general catalytic mechanism of serine proteases, far less is known about the roles of protein cofactors and membrane surfaces in regulating protease function. In our lab we are studying serine proteases in the blood clotting cascade with a goal of understanding the contributions of protein-protein and protein-phospholipid interactions to catalysis. Recently, we discovered that polyphosphate (a polymer of inorganic phosphate) potently modulates blood clotting and inflammation.
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?
- What are the mechanisms by which polyphosphate modulates blood clotting and inflammation?
- As a spinoff from these basic studies, we are working to develop:
- Improved hemostatic agents to treat surgical and traumatic bleeding
- New ways to prevent thrombosis without the severe bleeding risk associated with conventional anticoagulant drugs
- Improved diagnostic tests for identifying persons at risk of thrombotic disease