Ph.D., Boston University (Molecular Biology)
Academic Rank: Professor
Phone: 314-977-9240 Fax: 314-977-9205
Lab Web Page Link(s):
Primary Area of Cardiovascular Research Interest
Related Areas of Cardiovascular Research Interest
-Coagulation proteases and endothelial receptors structure-function
Summary of Cardiovascular Research Interest
Proteases of the coagulation cascade are a series of structurally similar trypsin-like enzymes which normally exist in the circulatory system as inactive precursors and are only activated when the integrity of the blood vessel is compromised. The cascade is initiated when a natural cell surface membrane protein called tissue factor, which is not normally found in the circulatory system, becomes available for interaction with factor VII. The factor VII-tissue factor complex activates itself and two other factors, IX and X, to their functional active forms (IXa and Xa). Factor Xa in the presence of its specific cofactor, factor Va, activates prothrombin to thrombin. Thrombin then cleaves fibrinogen to form a blood clot.
For maintenance of normal hemostasis, thrombin generation must be regulated and the activities of the coagulant enzymes following clot formation must be neutralized and subsequently removed from circulation in order to assure that they will not generate unnecessary blood clots that would occlude the vessels. Two pathways are known to regulate the coagulation cascade. The first pathway, called protein C pathway is initiated when thrombin binds to a cell surface membrane protein called thrombomodulin (TM), present on the surface of the endothelial cells that line blood vessels. Thrombin in complex with TM no longer clots fibrinogen, but instead converts protein C to activated protein C (APC). APC is a potent anticoagulant. It shuts down thrombin generation by degrading the cofactors Va and VIIIa, which are essential for thrombin generation.
In the second pathway, protease inhibitors present in plasma regulate the proteolytic function of the coagulation proteases by directly binding to the active center of the enzymes and trapping them in the form of inactive complexes. A deficiency in the components of either pathway is associated with increased risk of thrombosis with possible severe consequences including heart attacks, strokes and pulmonary emboli. Antithrombin is a serine protease inhibitor that is known to be the primary regulator of the clotting cascade in the second pathway. Its inhibitory activity is greatly enhanced when it binds to the heparin-like molecules present on the vessel wall. This is the basis for the widespread use of heparin, as the primary anticoagulant drug in the treatment of thrombotic complications. Our research is focused on understanding how factor Xa, thrombin and APC specifically interact with their target cofactors, substrates and inhibitors; and how heparin enhances the inhibitory function of antithrombin in regulation of the proteolytic activities of two key clotting enzymes, factor Xa and thrombin. We employ biophysical, biochemical and molecular biological methods to study these questions.