PROTHROMBOTIC EFFECTS IN LIPOPROTEIN-A

本应用程序的目的是探索 先前观察提示的Lp(A)的血栓前活性， 其中许多是在申请者的实验室制造的，表明 那：1)apo(A)在结构上与 纤溶酶原；2)Lp(A)和纤溶酶原一样，在体外与纤维蛋白结合 与纤溶酶原和组织型纤溶酶原激活剂竞争 用于纤维蛋白结合；以及3)内皮细胞培养系统。 Lp(A)与纤溶酶原竞争结合 受体。拟议的研究将包括三项基础研究和一项 临床部分都是为了检查血栓前状态 Lp(A)的位势。第一个组成部分，将在 芝加哥大学，将由Angelo M.Scanu博士和 Gunther Fless和将继续探索结构和 载脂蛋白B100-载脂蛋白(A)复合体在正常和 高甘油三酯血症状态并提供起源于 来自这些研究，用于计划中的实验 实验2和实验3.组成部分2，将在哈佛大学进行 医学院将由约瑟夫·洛斯卡尔佐博士领导，他将 继续研究Lp(A)影响 纤溶系统。第三部分将在 斯克里普斯医学研究所，将由爱德华博士领导 并将处理LP(A)对 纤溶酶原受体的结合。临床组件将使 Brigham选拔的血栓形成素质患者的应用 和哈佛妇女医院(约瑟夫·洛斯卡尔佐博士)和 芝加哥大学医院和诊所(克里斯托弗博士 Zarins)，以便在临床层面上检验推导出的假说 来自体外研究。这项多学科的研究 依赖于该领域的最新发现，初步 申请人的意见，以及既定的结案陈词 他们之间的合作将架起基础和临床之间的桥梁 试图确定动脉粥样硬化是如何发生的 脂蛋白Lp(A)影响或调节血栓/纤溶 机制。

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.