Mechanisms of Hemostatic Protease Inhibition by Serpins

丝氨酸蛋白酶抑制剂抑制止血蛋白酶的机制

基本信息

  • 批准号:
    7173010
  • 负责人:
  • 金额:
    $ 29.23万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-01-15 至 2010-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The long-term goal is to define the molecular mechanisms of thrombin (T) inhibition by the serpins, heparin cofactor II (HCII) and plasminogen activator inhibitor-1 (PAI-1), implicated in arterial thrombosis. Thrombin localized on fibrin (Fbn) and the glycosaminoglycans (GAGs) dermatan sulfate (DS) and heparin, reacts with HCII and platelet PAI-1, in GAG-accelerated mechanisms different from thrombin inhibition by antithrombin (AT), accelerated by high affinity heparin, present only in trace amounts. Unlike AT, HCII is a unique inhibitor of arterial thrombosis, as only HCII in the presence of DS is capable of inhibiting Fbn-bound thrombin. Thrombin exosites I and II are hypothesized to play different roles in these processes. Exosite I binds HCII and PAI-1 directly, whereas exosite II - heparin binding may modulate HCII and PAI-1 turnover. These steps are absent in the T - AT reaction. DS bound outside exosite II is hypothesized to act as template for inhibition by HCII of exosite ll-blocked thrombin, meizothrombin (MzT), and MzT(desFI). The identity of this site; the HCII and PAI-1 substrate pathways; the mechanisms of DS-selective inhibition of Fbn-bound thrombin by HCII, and of fibrinogen (Fbg) and Fbn regulation of thrombin inhibition by PAI-1 are all unknown. The studies will resolve these significant gaps, by using fluorescence equilibrium binding, steady-state and rapid kinetics with native thrombin, HCII and PAI-1, and specific loss-of- function mutants. They will test the hypotheses: that the exosite roles in the GAG-catalyzed thrombin inactivation mechanisms by HCII, PAI-1 and AT are distinctly different; that GAG binding outside exosite II on thrombin mediates inhibition by HCII; and that Fbg and Fbn regulate thrombin inhibition by these serpins differentially. Specific aims are: (1) To quantitate binding and chemical steps in the sequence of molecular events in the GAG-catalyzed thrombin inactivation and substrate pathways of HCII and PAI-1, compared to AT; (2) To characterize the DS-binding site outside exosite II in thrombin and MzT, and its role in thrombin and MzT inhibition; and (3) To determine the contributions of Fbg and Fbn binding to exosite I and GAGs in thrombin protection from HCII, PAI-1, and AT. These mechanism-based studies are relevant to understanding the selective, localized regulation of thrombin activity by HCII and PAI-1, and serpin turnover, in arterial clots. They may facilitate development of novel anticoagulants based on HCII and DS specifically targeted to arterial thrombosis
描述(由申请方提供):长期目标是确定动脉血栓形成中涉及的丝氨酸蛋白酶抑制剂、肝素辅因子II(HCII)和纤溶酶原激活物抑制剂-1(派-1)抑制凝血酶(T)的分子机制。凝血酶位于纤维蛋白(Fbn)和糖胺聚糖(GAG)、硫酸皮肤素(DS)和肝素上,与HCII和血小板派-1反应,其GAG加速机制不同于抗凝血酶(AT)对凝血酶的抑制,高亲和力肝素加速,仅以痕量存在。与AT不同,HCII是一种独特的动脉血栓形成抑制剂,因为只有在DS存在下HCII才能抑制Fbn结合的凝血酶。假设凝血酶外泌位点I和II在这些过程中发挥不同的作用。外切位点I直接结合HCII和派-1,而外切位点II -肝素结合可调节HCII和派-1周转。这些步骤在T-AT反应中不存在。假设DS结合在外部位点II外部作为模板,用于通过HCII抑制外部位点II阻断的凝血酶、甲藻凝血酶(MzT)和MzT(desFI)。本网站的标识; HCII和派-1底物途径; HCII对Fbn结合的凝血酶的DS选择性抑制以及派-1对凝血酶抑制的纤维蛋白原(Fbg)和Fbn调节的机制都是未知的。这些研究将通过使用荧光平衡结合,稳态和快速动力学与天然凝血酶,HCII和派-1,和特定的功能丧失突变体来解决这些重大的差距。他们将测试以下假设:外部位点的作用在GAG催化的凝血酶失活机制的HCII,派-1和AT是明显不同的; GAG结合外部位点II对凝血酶介导的抑制HCII;和Fbg和Fbn调节凝血酶抑制这些丝氨酸蛋白酶抑制剂的差异。具体目标是:(1)与AT相比,定量在GAG催化的凝血酶失活和HCII和派-1的底物途径中的分子事件序列中的结合和化学步骤;(2)表征凝血酶和MzT中外部位点II外的DS结合位点,及其在凝血酶和MzT抑制中的作用;(3)确定Fbg和Fbn与胞外位点I和GAG的结合在凝血酶保护HCII、派-1和AT中的作用。这些机制为基础的研究是相关的,以了解选择性,局部调节凝血酶活性的HCII和派-1,和丝氨酸蛋白酶抑制剂营业额,在动脉血栓。它们可能有助于开发基于HCII和DS的新型抗凝剂,专门针对动脉血栓形成

项目成果

期刊论文数量(0)
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INGRID M VERHAMME其他文献

INGRID M VERHAMME的其他文献

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{{ truncateString('INGRID M VERHAMME', 18)}}的其他基金

Roles of fibrin(ogen) in conformational activation of hemostatic proteinase precursors
纤维蛋白(原)在止血蛋白酶前体构象激活中的作用
  • 批准号:
    10453034
  • 财政年份:
    2022
  • 资助金额:
    $ 29.23万
  • 项目类别:
Roles of fibrin(ogen) in conformational activation of hemostatic proteinase precursors
纤维蛋白(原)在止血蛋白酶前体构象激活中的作用
  • 批准号:
    10620293
  • 财政年份:
    2022
  • 资助金额:
    $ 29.23万
  • 项目类别:
Mechanisms of Glycosaminoglycan-Catalyzed Protease Inactivation by Serpins
丝氨酸蛋白酶抑制剂 (Serpin) 糖胺聚糖催化的蛋白酶灭活机制
  • 批准号:
    9335436
  • 财政年份:
    2016
  • 资助金额:
    $ 29.23万
  • 项目类别:
Mechanisms of Glycosaminoglycan-Catalyzed Protease Inactivation by Serpins
丝氨酸蛋白酶抑制剂 (Serpin) 糖胺聚糖催化的蛋白酶灭活机制
  • 批准号:
    9175213
  • 财政年份:
    2016
  • 资助金额:
    $ 29.23万
  • 项目类别:
Mechanisms of Hemostatic Protease Inhibition by Serpins
丝氨酸蛋白酶抑制剂抑制止血蛋白酶的机制
  • 批准号:
    7837515
  • 财政年份:
    2009
  • 资助金额:
    $ 29.23万
  • 项目类别:
Mechanisms of Hemostatic Protease Inhibition by Serpins
丝氨酸蛋白酶抑制剂抑制止血蛋白酶的机制
  • 批准号:
    7540399
  • 财政年份:
    2006
  • 资助金额:
    $ 29.23万
  • 项目类别:
Mechanisms of Hemostatic Protease Inhibition by Serpins
丝氨酸蛋白酶抑制剂抑制止血蛋白酶的机制
  • 批准号:
    7754418
  • 财政年份:
    2006
  • 资助金额:
    $ 29.23万
  • 项目类别:
Mechanisms of Hemostatic Protease Inhibition by Serpins
丝氨酸蛋白酶抑制剂抑制止血蛋白酶的机制
  • 批准号:
    7047586
  • 财政年份:
    2006
  • 资助金额:
    $ 29.23万
  • 项目类别:
Mechanisms of Hemostatic Protease Inhibition by Serpins
丝氨酸蛋白酶抑制剂抑制止血蛋白酶的机制
  • 批准号:
    7338327
  • 财政年份:
    2006
  • 资助金额:
    $ 29.23万
  • 项目类别:

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