The function of the fibrinolysis system is to gradually eliminate existing blood clots and protect the fluidity of normal blood vessels. Recent advances in our understanding of fibrinolysis have resulted in the development of thrombolytic drugs which can be used to accelerate thrombus removal in heart attack and stroke. This research proposal concerns the proteinases, proteinase inhibitors, and cofactors that interact in normal fibrinolysis and thrombolytic therapy.
The first aim i s to understand the reaction of the thrombolytic complex, streptokinase-plasmin(ogen)(SkPl), preparations and on the importance of cofactor such as fibrinogen, fibrin digestion products and platelet surfaces. The variability in the reaction of SkPl with alpha-macroglobulins from different species will be explored. Small protein-polymer conjugates and chemically modified forms of naturally occurring human alpha2- macroglobulin will be studied as potential therapeutic agents for the regulation of fibrinolysis. A second focus of this program will be to study the synthesis, secretion, and distribution of plasminogen and the fibrinolysis inhibitors. Synthesis experiments will utilize primary culture of hepatocytes, thin slices of whole rate liver, the Hep-G2 cell line, and central nervous system tumors that have previously been shown to synthesize various fibrinolysis proteins. Modulation of synthesis by factors generated during thrombolysis, such as fibrinogen fragment D, alpha2-antiplasmin- plasmin complex an hepatocyte stimulating factor, will be studied. Distribution experiments, performed in mice, will focus on the organ and cellular levels with special attention directed towards the liver and brain. In each case, the function of cell surface macromolecules in plasminogen activation and plasmin inhibition will be explored. These and related experiments will be performed in a well equipped, independently functioning laboratory at the University of Virginia. During the next five years, the applicant and the institution share the objective of developing this laboratory into a well established center for hemostasis research in this country.
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