Math Biology Seminar Abstracts

Monday May 13, 2002 3:05 pm LCB 323

Speaker: John W. Weisel, Ph.D. Professor of Cell and Developmental Biology University of Pennsylvania School of Medicine

Title: `` Fibrin, Fibrinolysis, and Platelet Aggregation: New Approaches and Unexpected Results?''

Abstract: Recent results will be presented from several research projects in my lab related to the molecular and cellular mechanisms of blood coagulation and fibrinolysis, as analyzed through the use of various biophysical and structural techniques, including visualization of molecules and supramolecular aggregates and measurements of mechanical properties of cellular and extracellular structures. Fibrin clot formation begins with cleavage of fibrinopeptides from fibrinogen, yielding fibrin monomers, which associate to form oligomers and eventually two-stranded protofibrils, which aggregate laterally into fibers that branch to make a three-dimensional network. Molecular mechanisms of the dissolution of the clot by the fibrinolytic system essentially reverse this process. Much has been known about the biochemical mechanisms involved but not about the physical process of fibrinolysis. Our recent studies of the physical process of lysis by transmission and scanning electron microscopy and confocal light microscopy revealed some big surprises. Rather than being digested from the outside inward, fibers are transected laterally, removing whole chunks of the fibers. As cleavage occurs, protofibrils dissociate, yielding a lacy network of thin structures. Platelets have a dramatic effect on the structure of the fibrin surrounding platelet-rich areas, and those regions are digested much more slowly, resulting in meandering channels and islands as fibrinolysis proceeds. Antithrombotic drugs reverse this effect and thus have a striking effect on lysis. Platelet aggregation is also a major focus of my research, particularly interactions between fibrinogen and its integrin receptor on the platelet surface. We have developed a model system based on laser tweezers enabling us to determine the rupture force of individual ligand-receptor pairs by using either purified proteins or integrin on the surface of living platelets. We can determine the activation state of integrins at the level of single molecules and examine the effects of inhibitors. We found that activation of platelets increased the accessibility but not the adhesion strength of single integrin molecules, indicating that there are only two important activation states so that this process is basically all-or-none. The results of these studies have implications for basic mechanisms of protein-protein and protein-cell interactions as well as for clinical aspects of hemostasis, thrombosis and atherosclerosis.

For more information contact J. Keener, 1-6089