Efficacy of Kunitz Domain 1 variants of TFPI-2 as novel antifibrinolytic agents

TFPI-2 Kunitz 结构域 1 变体作为新型抗纤维蛋白溶解剂的功效

基本信息

  • 批准号:
    7792289
  • 负责人:
  • 金额:
    $ 19.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-04-01 至 2012-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal remains to test a novel and unique inhibitor of plasmin that has the potential to reduce severe bleeding in major surgery as well as in coagulopathy. Until recently, another inhibitor of plasmin, called aprotinin was used as an antifibrinolytic agent to reduce blood loss in cardiac, organ transplant, orthopedic and vascular surgery. In fact, aprotinin was the only FDA-approved drug to reduce blood transfusion in cardiac surgery with cardiopulmonary bypass. Three meta-analyses of aprotinin reported in 1999 indicated that aprotinin decreased mortality (by two fold), the incidence of surgical reexploration, as well as blood transfusions. However, in a recent multi-institutional study, aprotinin was reported to significantly increase the risk of renal, cardiovascular and neurological injury, based on its ability to inhibit kallikrein and therefore kinin formation, leading to disturbed autoregulation of organ blood flow. Using crystallography, molecular modeling and biochemical approaches, we generated two variants of the first Kunitz domain (KD1) of human tissue factor pathway inhibitor-2 (TFPI-2) that are significantly more potent inhibitors of plasmin as compared to the wild-type KD1 or to the full-length TFPI-2. Preliminary data revealed the unique ability of KD1 variants to strongly inhibit human and mouse plasmin with minimal or no inhibition of kallikrein. Based upon this fundamental property of the KD1 variants, which provides a distinct advantage over aprotinin, we hypothesize that KD1 variants will be effective antifibrinolytic agents without causing significant organ injury related to the inhibition of kallikreins. The proposed studies are designed to determine the efficacy and toxicity of KD1 variants using two specific aims. In specific aim 1, we will express wild type KD1 and the two variants (one modified at P2' residue and the second at P1 and P2' residues) in E. coli, further characterize their binding to plasmin, tissue and plasma kallikreins and other proteases involved in the coagulation cascade. Further, we will obtain crystal structures to validate the molecular interactions between the KD1 variants and plasmin. In specific aim 2, we will compare the efficacy of the KD1 variants to aprotinin in reducing bleeding from large and small vessels in animal models. Further, we will study the toxicity of the KD1 variants to the vital organs in the animal models and compare it to aprotinin. We anticipate that KD1 variants will reduce total blood loss without having an adverse effect on organ function. The long term goals of this proposal are to study the efficacy and toxicity of KD1 variants in animal models of cardiac surgery with cardiopulmonary bypass. PUBLIC HEALTH RELEVANCE: In patients with open-heart surgery and organ transplant, there is significant blood loss due to breakdown of fibrin by plasmin. Aprotinin, an antifibrinolytic drug that has been used to inhibit plasmin was discontinued in 2007 as it was found to cause significant organ injury. Here, we are proposing to test a new drug that our laboratory has designed to reduce bleeding in high-risk cardiac surgery and transplant patients.
描述(由申请人提供):本申请的目标仍然是测试一种新颖独特的纤溶酶抑制剂,该抑制剂有可能减少大手术和凝血病中的严重出血。直到最近,另一种叫做抑酶蛋白的纤溶酶抑制剂被用作抗纤溶剂,以减少心脏、器官移植、骨科和血管手术中的失血。事实上,抑酶蛋白是fda批准的唯一一种在体外循环心脏手术中减少输血的药物。1999年报道的三个关于抑酶蛋白的荟萃分析表明,抑酶蛋白降低了死亡率(2倍)、手术再探查的发生率以及输血。然而,在最近的一项多机构研究中,抑肽蛋白被报道会显著增加肾脏、心血管和神经损伤的风险,这是基于抑肽蛋白抑制钾激肽的能力,从而抑制激肽的形成,导致器官血流的自我调节受到干扰。利用晶体学、分子建模和生化方法,我们生成了人组织因子途径抑制剂-2 (TFPI-2)的第一个Kunitz结构域(KD1)的两个变体,与野生型KD1或全长TFPI-2相比,它们是纤溶酶更有效的抑制剂。初步数据显示,KD1变体具有独特的能力,能够强烈抑制人和小鼠的纤溶酶,而很少或不抑制钾激肽。基于KD1变异体的这一基本特性,它比抑酶蛋白具有明显的优势,我们假设KD1变异体将是有效的抗纤溶药物,而不会引起与钾氨酸激酶抑制相关的显著器官损伤。拟议的研究旨在确定KD1变异的功效和毒性,有两个特定的目的。在具体目标1中,我们将在大肠杆菌中表达野生型KD1和两个变体(一个在P2‘残基上修饰,另一个在P1和P2’残基上修饰),进一步表征它们与纤溶蛋白、组织和血浆钾溶酶以及其他参与凝血级联的蛋白酶的结合。此外,我们将获得晶体结构来验证KD1变体与纤溶蛋白之间的分子相互作用。在具体目标2中,我们将比较动物模型中KD1变体与抑酶蛋白在减少大血管和小血管出血方面的功效。此外,我们将在动物模型中研究KD1变异对重要器官的毒性,并将其与抑蛋白蛋白进行比较。我们预计KD1变异将减少总失血量,而不会对器官功能产生不利影响。本研究的长期目标是在体外循环心脏手术动物模型中研究KD1变异的疗效和毒性。公共卫生相关性:在接受心脏直视手术和器官移植的患者中,由于纤溶蛋白分解纤维蛋白而导致大量失血。抑酶蛋白是一种用于抑制纤溶酶的抗纤溶药物,由于发现它会造成严重的器官损伤,于2007年停止使用。在这里,我们提议测试我们实验室设计的一种新药,用于减少高危心脏手术和移植患者的出血。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Structural biology of factor VIIa/tissue factor initiated coagulation.
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Madhu Satya Bajaj其他文献

Madhu Satya Bajaj的其他文献

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{{ truncateString('Madhu Satya Bajaj', 18)}}的其他基金

Efficacy of Kunitz Domain 1 variants of TFPI-2 as novel antifibrinolytic agents
TFPI-2 Kunitz 结构域 1 变体作为新型抗纤维蛋白溶解剂的功效
  • 批准号:
    7589884
  • 财政年份:
    2009
  • 资助金额:
    $ 19.25万
  • 项目类别:
REGULATION OF TISSUE FACTOR PATHWAY INHIBITOR EXPRESSION
组织因子途径抑制剂表达的调节
  • 批准号:
    2211397
  • 财政年份:
    1996
  • 资助金额:
    $ 19.25万
  • 项目类别:
REGULATION OF TISSUE FACTOR PATHWAY INHIBITOR EXPRESSION
组织因子途径抑制剂表达的调节
  • 批准号:
    6181932
  • 财政年份:
    1996
  • 资助金额:
    $ 19.25万
  • 项目类别:
REGULATION OF TISSUE FACTOR PATHWAY INHIBITOR EXPRESSION
组织因子途径抑制剂表达的调节
  • 批准号:
    6030356
  • 财政年份:
    1996
  • 资助金额:
    $ 19.25万
  • 项目类别:
REGULATION OF TISSUE FACTOR PATHWAY INHIBITOR EXPRESSION
组织因子途径抑制剂表达的调节
  • 批准号:
    2445017
  • 财政年份:
    1996
  • 资助金额:
    $ 19.25万
  • 项目类别:
REGULATION OF TISSUE FACTOR PATHWAY INHIBITOR EXPRESSION
组织因子途径抑制剂表达的调节
  • 批准号:
    2734937
  • 财政年份:
    1996
  • 资助金额:
    $ 19.25万
  • 项目类别:

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