Factor Xl in Vascular Thrombosis

血管血栓形成中的 XI 因子

基本信息

  • 批准号:
    7790577
  • 负责人:
  • 金额:
    $ 30.7万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-04-06 至 2011-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The protease factor Xla (fXIa) contributes to hemostasis by sustaining thrombin generation after initiation of blood coagulation. In addition to contributing to fibrin formation, fXIa promotes clot resistance to fibrinolysis in a process involving the proteinase TAFI. Several lines of evidence indicate fXIa contributes to pathologic coagulation. Elevated plasma levels of the fXIa precursor fXI are associated with increased risks for arterial and venous thrombosis in humans. We observed that fXI deficient mice are resistant to vascular occlusion in arterial injury models, indicating fXIa contributes to platelet rich thrombus formation. FXI binds to platelets in vitro, and is converted to fXIa by thrombin or factor XI la (fXlla). The importance of these interactions in vivo or in complex in vitro systems is not known, and the relative importance of thrombin and fXlla to fXI activation is not clear. FXI I deficiency does not cause a bleeding abnormality, indicating fXI is activated in vivo by other proteases. However, fXII deficient mice are resistant to arterial occlusion, raising the possibility that formation of a pathologic occlusive thrombus involves processes distinct from those involved in normal hemostasis. In Aim 1 of this proposal, we will use mice with deficiencies of fXI, fXII, and TAFI to investigate the importance of these proteins in models of pathologic coagulation. Using a panel of novel recombinant fXI variants to reconstitute fXI deficient mice, we will determine the importance of fXI interactions with platelets, thrombin and fXlla to these models, and look for alternative functions for fXI and fXII unrelated to classical coagulation pathways. In Aim 2, a murine fXI-dependent bleeding model will be used to determine if fXI interactions with platelets, thrombin and fXlla are required for hemostasis. In Aim 3 we will use human and murine platelet rich plasma systems to examine the importance of fXI and fXII to thrombin generation and platelet activation in vitro, with the primary goal of determining if there are differences between the two species. These studies will allow us to compare the importance of fXI, fXII and TAFI to normal hemostasis and to pathologic coagulation, and will provide valuable information regarding the mechanism(s) for fXI activation in complex systems. Ultimately, the work may demonstrate that fXI and/or fXII contribute in a substantive way to blood vessel occlusion, and are therefore, legitimate targets for novel investigative therapies to treat or prevent vascular thromboembolism in humans. Relevance: Anticoagulant drugs have been very beneficial for treating abnormal blood clots in a variety of diseases, but have the disadvantage of leaving the patient prone to serious bleeding. We are looking for new targets in blood for anticoagulation therapy that will not be associated with high bleeding risk.
描述(由申请人提供):蛋白酶因子XLA(FXIa)在开始凝血后通过维持凝血酶的生成而有助于止血。除了促进纤维蛋白的形成外,fXIa还在涉及蛋白酶Tafi的过程中促进血栓对纤溶的抵抗。多条证据表明fXIa与病理性凝血有关。血浆fXIa前体FXI水平的升高与人类动脉和静脉血栓形成的风险增加有关。我们观察到,在动脉损伤模型中,FXI缺陷小鼠对血管闭塞具有抵抗力,表明FXIa有助于富含血小板的血栓的形成。FXI在体外与血小板结合,并在凝血酶或凝血因子X1a(FX1a)的作用下转化为fXIa。这些相互作用在体内或复杂的体外系统中的重要性尚不清楚,凝血酶和fX11a对FXI激活的相对重要性也不清楚。FXI I缺乏不会导致出血异常,这表明FXI在体内被其他蛋白酶激活。然而,FXII缺陷小鼠对动脉闭塞具有抵抗力,这增加了病理性闭塞血栓的形成涉及不同于正常止血的过程的可能性。在这项建议的目标1中,我们将使用FXI、FXII和TAFI缺陷的小鼠来研究这些蛋白在病理性凝血模型中的重要性。使用一组新的重组FXI变异体来重建FXI缺陷小鼠,我们将确定FXI与血小板、凝血酶和FX11a相互作用对这些模型的重要性,并寻找FXI和FXII与经典凝血途径无关的替代功能。在目标2中,将使用小鼠FXI依赖的出血模型来确定是否需要FXI与血小板、凝血酶和fX11a的相互作用来止血。在目标3中,我们将使用人和小鼠富含血小板的血浆系统来检测FXI和FXII在体外凝血酶生成和血小板激活中的重要性,主要目的是确定这两个物种之间是否存在差异。这些研究将使我们能够比较FXI、FXII和TAFI对于正常止血和病理性凝血的重要性,并将提供关于复杂系统中FXI激活机制的有价值的信息(S)。最终,这项工作可能会证明FXI和/或FXII对血管闭塞有实质性的贡献,因此是治疗或预防人类血管血栓栓塞症的新型研究疗法的合法靶点。相关:抗凝药物对治疗各种疾病中的异常血栓非常有益,但缺点是容易导致患者严重出血。我们正在寻找血液中抗凝治疗的新靶点,这些靶点不会与高出血风险相关。

项目成果

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David Gailani其他文献

David Gailani的其他文献

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{{ truncateString('David Gailani', 18)}}的其他基金

Biochemistry and Pathophysiology of Factor XI and Contact Activation
XI 因子的生物化学和病理生理学以及接触激活
  • 批准号:
    10551290
  • 财政年份:
    2018
  • 资助金额:
    $ 30.7万
  • 项目类别:
Biochemistry and Pathophysiology of Factor XI and Contact Activation
XI 因子的生物化学和病理生理学以及接触激活
  • 批准号:
    10083646
  • 财政年份:
    2018
  • 资助金额:
    $ 30.7万
  • 项目类别:
Biochemistry and Pathophysiology of Factor XI and Contact Activation
XI 因子的生物化学和病理生理学以及接触激活
  • 批准号:
    10321924
  • 财政年份:
    2018
  • 资助金额:
    $ 30.7万
  • 项目类别:
Factor Xl in Vascular Thrombosis
血管血栓形成中的 XI 因子
  • 批准号:
    7586763
  • 财政年份:
    2007
  • 资助金额:
    $ 30.7万
  • 项目类别:
Factor XI in Thrombosis
血栓形成因子 XI
  • 批准号:
    9270121
  • 财政年份:
    2007
  • 资助金额:
    $ 30.7万
  • 项目类别:
Factor XI in Thrombosis
血栓形成因子 XI
  • 批准号:
    8600714
  • 财政年份:
    2007
  • 资助金额:
    $ 30.7万
  • 项目类别:
Factor XI in Thrombosis
血栓形成中的因子 XI
  • 批准号:
    8237528
  • 财政年份:
    2007
  • 资助金额:
    $ 30.7万
  • 项目类别:
Factor XI in Thrombosis
血栓形成中的因子 XI
  • 批准号:
    8403680
  • 财政年份:
    2007
  • 资助金额:
    $ 30.7万
  • 项目类别:
Factor Xl in Vascular Thrombosis
血管血栓形成中的 XI 因子
  • 批准号:
    7393736
  • 财政年份:
    2007
  • 资助金额:
    $ 30.7万
  • 项目类别:
Factor XI in Thrombosis
血栓形成因子 XI
  • 批准号:
    9226006
  • 财政年份:
    2007
  • 资助金额:
    $ 30.7万
  • 项目类别:

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