PROTHROMBOTIC EFFECTS IN LIPOPROTEIN-A

本申请的目的是探索的机制， Lp（a）的促血栓形成活性由先前的观察结果提示， 其中许多是在申请人的实验室中制备的，表明 （1）apo（a）与 纤溶酶原; 2）Lp（a），像纤溶酶原一样，在体外与纤维蛋白结合 并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;和3）在内皮细胞培养系统中。 Lp（a）与纤溶酶原竞争结合纤溶酶原 受体的 拟议的研究将有三个基本和一个 临床部分都是针对检查血栓前 Lp（a）的电位。 第一个组成部分将在 芝加哥大学，将由安杰洛M。斯卡努和 冈瑟·弗莱斯将继续探索结构和 apoB 100-apo（a）复合物在正常和 高血糖状态，并提供产品来源 从这些研究中，用于计划在 实验2和3。 组成部分2，将在哈佛进行 医学院，将由约瑟夫Loscalzo博士谁将领导 继续研究Lp（a）影响 纤溶系统 构成部分3将在 斯克里普斯医学研究所将由爱德华博士领导 犁，并将处理竞争机制的Lp（a）为 纤溶酶原受体的结合。 临床部分将使 使用来自Brigham的具有血栓形成素质的患者 和哈佛妇女医院（约瑟夫·洛斯卡尔佐博士）以及 芝加哥大学医院和诊所（克里斯托弗博士 Zarins），以便在临床水平上检验所得出的假设 来自体外研究。 这项多学科研究， 依赖于该领域的最新发现， 申请人的意见，并在确定的结束 他们之间的合作将在基础和临床之间架起桥梁。 活动，试图建立如何动脉粥样硬化 脂蛋白，Lp（a）影响或调节血栓形成/纤维蛋白溶解 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.