ANTICOAGULANT THROMBINS IN VITRO AND IN VIVO

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 根据美国疾病控制与预防中心的统计数据，血栓形成(血液在血管中凝结)在美国一半以上的死亡中起着直接、直接和因果的作用，例如心脏病发作、中风、肺栓塞、外周动脉疾病、感染中的播散性血栓形成和/或转移性癌症、脑血管性痴呆等。因此，血栓形成可以说是美国最重要的悬而未决的医学问题。本项目致力于确定合理设计的蛋白C激活剂(PCA)新酶在血栓性疾病中的治疗(抗血栓)潜力。促凝血剂需要Na+结合，但凝血酶的抗凝血活性不需要。这一发现使我们能够设计出新的凝血酶类似物，选择性地降低它们的促凝血特性。我们开始在灵长类动物模型设计者的PCAs中对天然抗凝剂蛋白C进行高选择性测试，以评估它们对血栓形成和止血的影响。与预测一致的是，几个分子显示出抗凝和抗血栓作用。我们一直在将这些突变体中的一些与直接使用活化蛋白C和其他抗血栓药物的效果进行比较。最近完成的一系列研究揭示了蛋白C激活酶W215A/E217A的药理潜力，它是一种36kD的凝血酶类似物。在我们的灵长类动物模型中，W215A/E217A在防止血栓形成方面被证明比抗凝剂药物依诺肝素有效两到三个数量级，而且明显更安全。事实上，W215A/E217A是迄今已知的最有效的抗血栓分子。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Based on CDC statistics, thrombosis (clotting of blood in blood vessels) has immediate, direct, and causal role in more than half of all deaths in the U.S., e.g. in heart attack, stroke, pulmonary embolism, peripheral arterial disease, disseminated thrombosis in infections and/or metastatic cancer, cerebrovascular dementia, etc. Thus, thrombosis is arguably the most important unresolved medical problem in this country. This project is focused on determining the therapeutic (antithrombotic) potential of using rationally designed protein C activator (PCA) neo-enzymes in thrombotic diseases. Na+ binding is required for the procoagulant, but not the anticoagulant activity of thrombin. This discovery has enabled us to engineer novel thrombin analogs selectively compromised in their procoagulant properties. We started testing in our primate model designer PCAs with high selectivity toward the natural anticoagulant, protein C, to assess their effects on thrombosis and hemostasis. Consistent with the predictions, several molecules have shown anticoagulant and antithrombotic effects. We have been comparing the effects of some of these mutants with the direct administration of activated protein C and other antithrombotic agents. The latest completed series of studies revealed the pharmacological potential of the protein C activator enzyme, W215A/E217A, which is a 36kD thrombin analog. W215A/E217A proved to be two to three orders of magnitude more potent and significantly safer in our primate model than the anticoagulant drug, enoxaparin, in the prevention of thrombus formation. In fact, W215A/E217A is the most potent antithrombotic molecule known to date.