BPTI-MUTANTS AS NOVEL ANTITHROMBOTIC AGENTS

心血管疾病是#年死亡和发病的主要原因。 工业化世界。血栓形成的原因是激活了 凝血级联是常见的病因。 构成这种疾病的三个主要类别包括：冠状动脉 导致急性心肌梗死(AMI)的动脉疾病， 脑血管疾病导致中风和静脉血栓形成 通常会导致肺栓塞。只有数量有限的 可用于治疗这些疾病的治疗方法都不是 压倒性的有效。在第二阶段的建议中，我们建议 选择性凝血抑制剂的改进与评价 因子VIIa和Xa成功地从一个突变体中获得 昆尼茨丝氨酸蛋白酶抑制物在第一阶段的作用 奖助金。这些研究将包括现场定向和随机 诱变以提高抑制剂的效力和选择性 基于酶的三维结构测定 抑制剂复合体及其在体内外的全面评价 精选化合物的抑制作用和抗血栓作用 已建立的实验性全动物血栓形成模型中的抑制剂。 预计一种新颖的、临床上更有效的 作为这些研究的结果，抗血栓治疗将会出现。

Cardiovascular disease is the major cause of mortality and morbidity in the industrialized world. Thrombosis resulting from the activation of the blood coagulation cascade is the common etiology which underlies the three main categories that comprise this disease which includes: coronary artery disease leading to acute myocardial infarction (AMI), cerebrovascular disease leading to stroke and venous thrombosis which often leads to pulmonary embolism. There are only a limited number of therapies available to treat these diseases none of which are overwhelmingly effective. We propose in this phase II proposal to improve upon and evaluate the selective inhibitors of blood coagulation factors VIIa and Xa successfully engineered from mutants of a prototypical Kunitz serine protease inhibitor in the phase I portion of the grant. These studies will include site directed and random mutagenesis to improve the potency and selectivity of the inhibitors based on the three dimensional structural determination of an enzyme inhibitor complex and the full in vitro and in vivo evaluation of the inhibitory properties and antithrombotic effectiveness of selected inhibitors in established experimental whole animal models of thrombosis. It is anticipated that a novel and more clinically effective antithrombotic treatment will emerge as a result of these studies.