Biochemistry and Pathophysiology of Factor XI and Contact Activation

项目总结 凝血因子Xia(FXIa)是血浆蛋白因子XI(FXI)的一种酶形式，参与凝血酶的生成 主要通过催化激活因子IX(FIX)。这似乎反映了主机中的辅助角色 对损伤的止血反应，因为FXI缺乏至多会导致相对轻微的出血障碍。尽管它的 止血作用有限，来自人类人口研究和动物模型的越来越多的证据支持 前提是FXI对静脉和动脉血栓形成有实质性贡献。这导致了相当大的 对fXIa的治疗抑制感兴趣，希望这样的策略将产生有用的抗血栓药 止血效果比目前使用的抗凝剂如肝素、华法林和 较新的直接口服抗凝剂。FXI在结构上不同于维生素K依赖的凝血 形成凝血酶生成机制的核心的蛋白酶。事实上，FXI起源于对 前激肽释放酶(PK)基因，-激肽释放酶的前体。PK，连同因子XII(FXII)和HIGH 分子量激肽原(HK)形成激肽释放酶-激肽系统(KKS)，KKS是天然免疫的组成部分 对损伤产生促炎性多肽的反应。作为PK的同源物，FXI保留了 母体分子的活性。然而，FXI已经获得了独特的功能，这些功能促进了它与 凝血酶的生成机制。我们当前的工作模式是FXI作为双向 凝血酶生成和KKS之间的接口，这使它处于影响效果的位置 两个系统的血栓形成和炎症过程。我们实验室的工作旨在建立一个 更好地了解FXI的生物化学、分子生物学和病理生理学及其相互关系 与凝血酶生成和KKS有关。我们对这个问题采取了广泛的方法，这反映在 此应用程序中描述的三个重点领域。焦点领域1研究重要的结构-功能 FXI分子中与其在流动血液中的活性相关的关系。焦点区域2将调查 FXI、FXII、PK和HK在小鼠血栓形成和脓毒症模型中的作用我们还将 研究FXI在调节凝血因子IX缺乏小鼠(血友病B模型)出血倾向中的作用。 并继续最近的观察，血管系统中的大多数FXI形成了一个非循环池 与血管壁相关。最后，重点领域3的工作旨在更好地理解 FXII，一种蛋白水解酶(FXIIa)的前体，激活FXI和PK，促进血栓炎症 流程。我们强烈地感觉到我们范德比尔特大学实验室的专业知识，以及 与我们合作了十多年的学术界和工业界的合作者，使我们处于一个独特的 对血栓形成研究领域作出重要贡献的职位，目标是更好地提供信息 努力开发新的抗血栓疗法。

PROJECT SUMMARY Factor XIa (fXIa), the protease form of the plasma protein factor XI (fXI), contributes to thrombin generation primarily by catalyzing activation of factor IX (fIX). This appears to reflect an ancillary role in the host hemostatic response to injury, as fXI deficiency causes, at most, a relatively mild bleeding disorder. Despite its limited role in hemostasis, mounting evidence from human population studies and animal models support the premise that fXI contributes substantively to venous and arterial thrombosis. This has lead to considerable interest in therapeutic inhibition of fXIa, with the hope that such a strategy will produce a useful antithrombotic effect, with a smaller impact on hemostasis than currently used anticoagulants such as heparin, warfarin and newer direct oral anticoagulants. FXI is structurally distinct from the vitamin K-dependent coagulation proteases that form the core of the thrombin generation mechanism. Indeed, fXI arose from a duplication of the gene for prekallikrein (PK), the precursor of the protease -kallikrein. PK, along with factor XII (fXII) and high molecular weight kininogen (HK) form the kallikrein-kinin system (KKS), a component of the innate immune response that generates proinflammatory peptides in response to injury. As a homolog of PK, fXI retains activities of the parent molecule. However, fXI has acquired unique features that facilitate its interactions with the thrombin generation mechanism. Our current working model is that fXI functions as a bi-directional interface between thrombin generation and the KKS, and that this places it in a position to influence the effects of both systems on thrombotic and inflammatory processes. Work in our laboratory is directed at establishing a better understanding of the biochemistry, molecular biology and pathophysiology of fXI, and its relationships with thrombin generation and the KKS. We take a broad approach to this problem, which is reflected in the three Focus Areas described in this application. Focus Area 1 investigates important structure-function relationships in the fXI molecule that are relevant to its activity in flowing blood. Focus Area 2 will investigate the contributions of fXI, fXII, PK and HK to thrombus formation and sepsis in mouse models. We will also investigate the role of fXI in modulating bleeding tendency in mice lacking factor IX (a model of hemophilia B), and pursue a recent observation that the majority of fXI in the vasculature forms a non-circulating pool associated with the blood vessel wall. Finally, work in Focus Area 3 is directed at a better understanding of fXII, the precursor of a protease (fXIIa), that activates fXI and PK, and that contributes to thrombo-inflammatory processes. We strongly feel that the expertise in our laboratory at Vanderbilt University, and the stellar group of collaborators in academia and industry that have worked with us for over a decade, place us in a unique position to make important contributions to the field of thrombosis research, with the goal of better informing efforts to develop novel antithrombotic therapies.