The purpose of this application is to explore the mechanisms of the prothrombotic activity of Lp(a) prompted by previous observations, many of them made in the laboratories of the applicants, indicating that: 1) apo(a) has striking structural similarities with plasminogen; 2) Lp(a), like plasminogen, binds in vitro to fibrin and competes with plasminogen and tissue-type plasminogen activator for fibrin binding; and 3) in endothelial cell culture systems. Lp(a) competes for the binding of plasminogen with the plasminogen receptor. The proposed studies will have three basic and one clinical component all directed at examining the prothrombotic potential of Lp(a). The first component, to be carried out at the University of Chicago, will be headed by Drs. Angelo M. Scanu and Gunther Fless and will continue to explore the structural and functional roles of the apoB100-apo(a) complex in normo- and hypertriglyceridemic states and provide the products originating from those studies for use in the experiments planned in experiments 2 and 3. Component 2, to be carried out at Harvard Medical School, will be headed by Dr. Joseph Loscalzo who will pursue studies on the mechanisms whereby Lp(a) influences the fibrinolytic system. Component 3 will be carried out at the Scripps Medical Research Institute, will be headed by Dr. Edward Plow and will deal with mechanisms of competition by Lp(a) for the binding of plasminogen receptor. The clinical component will make use of patients with thrombotic diathesis selected from Brigham and Women's Hospital at Harvard (Dr. Joseph Loscalzo) and the University of Chicago Hospitals and Clinics (Dr. Christopher Zarins) in order to test on the clinical level hypotheses derived from the in vitro studies. This multidisciplinary study that relies on recent discoveries in the field, on preliminary observations by the applicants, and on established close collaborative efforts among them will bridge basic and clinical activities in an attempt to establish how the atherogenic lipoprotein, Lp(a) affects or modulates thrombotic/fibrinolytic mechanism.
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