Biochemistry, Enzyme action, Gene regulation, Knockout, Mouse, Polymorphism, Protein structure
A dynamic balance exists between the processes that form a blood clot at the site of blood vessel injury (coagulation) and the processes responsible for removing the clot once healing has occurred (fibrinolysis). This equilibrium, referred to as hemostasis, is required to prevent excessive blood loss from a wound (bleeding) while avoiding occlusion of normal blood vessels (thrombosis). My laboratory is involved in studying the contribution of certain plasma clotting factors to the formation of fibrin clots in normal and pathologic conditions. We are particularly interested in the plasma serine proteases factors IX and XI. These enzymes appear to be required for consolidating the hemostatic process after initial clot formation. Excessive activity of either protein has been linked to formation of pathologic blood vessel thrombosis. Utilizing a combination of site-directed mutagenesis, production of recombinant proteins in mammalian tissue culture, enzymology and classic coagulation assays we are investigation structure/function relationships as they relate to the activation, the activity, and binding interactions involving factors IX and XI. We are applying similar approaches to investigations of the proteases responsible for converting inactive factor XI to the active form factor XIa.
More recently, we have been investigating the contributions of factors IX and XI to hemostasis and thrombosis in vivo, using factor IX and factor XI deficient mice. These proteins appear to play important roles in the formation of abnormal occlusive thrombi in mouse models, and may be attractive targets for drugs to prevent or treat blood vessel thrombosis in human patients.