Physical exposure of blood to extraluminal matrices upon vascular injury triggers a series of events that leads to the formation of a hemostatic plug. During this dynamic process, platelets rapidly accumulate, activate and expose a procoagulant surface for thrombin-catalyzed fibrin generation to seal the wound. While the generation of thrombin and activation of platelets are essential for normal hemostasis, under pathological conditions, uncontrolled progression of a mechanistically similar process results in occlusion of blood vessels and thrombosis. Thrombosis can lead to myocardial infarction, pulmonary embolism or stroke. Proteins including protein C (PC) are essential for the regulation of thrombosis; however, the exact mechanisms that normally prevent the formation of occlusive thrombi following thrombogenic triggers are not clear. Preliminary data identify apolipoprotein E receptor 2 (ApoER2) and glycoprotein (GP)Ibalpha as novel receptors for PC. I hypothesize that these receptors play a role in augmenting the PC anticoagulant system, thus limiting thrombus growth. As elegant studies, including site-directed mutagenesis of coagulation enzymes, have failed to predict key molecular events observed in vivo, the role of coagulation factor-platelet interactions in the process of thrombosis must be assessed in the presence of live cells, under rheologically-relevant conditions.In Aim 1, I will map the regions of PC integral for interactions with the platelet receptors ApoER2 and GPIbalpha and determine the affinity of platelet-PC binding in the presence of physiological shear stress.In Aim 2, I will determine the functional significance of platelet-PC binding by characterizing the roles of ApoER2 and GPIbalpha in 1) (A)PC recruitment to the platelet surface and 2) APC generation and function on the platelet surface.Understanding the mechanisms governing and consequences of platelet-PC interactions may promote the pharmaceutical development of a novel class of targeted anticoagulants augmenting the anticoagulant properties of the thrombus surface.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2009 → 04/01/2010|