Role of Von Willebrand Factor in Platelet Thrombosis Formation

血管性血友病因子在血小板血栓形成中的作用

基本信息

  • 批准号:
    7995814
  • 负责人:
  • 金额:
    $ 53.67万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-08-15 至 2015-04-30
  • 项目状态:
    已结题

项目摘要

In this application we propose to continue efforts aimed at elucidating von Willebrand factor (VWF) structure and function focusing on four aims. In aim 1 we will test whether structural elements in the VWF Al domain (VWFA1) can differentially regulate specific adhesive properties. Preliminary data indicate that the interaction of glycoprotein (GP) Iba with VWFA1 immobilized onto a surface, leading to platelet adhesion, may occur through different mechanisms as compared to binding of soluble VWF mediating platelet aggregation. Our goal is to define the distinctive structural elements underlying the initiation and regulation of specific VWF activities and establish their functional relevance in models of vascular injury. In aim 2 we intend to ascertain whether a-thrombin can act as a physiologic modulator of VWF adhesive properties. We hypothesize that VWFA1 and a-thrombin establish inter-molecular contacts when bound to the same GPIba receptor, and this may influence the stability of the VWFA1-GPIba bond independently of shear stress. We propose to identify the VWFA1 residues that support the interaction with a-thrombin bound to GPIba, thus defining a novel mechanism for the regulation of VWF function during thrombogenesis. In aim 3 we propose to evaluate whether a specific IgG found in the human population is a modulator of VWF activity. We have identified in human and mouse blood a specific IgG that binds selectively to VWFA1, and obtained preliminary evidence that this IgG may play a role in thrombus formation. Our goal is to characterize the structure of the specific IgG, define the mode of interaction with VWFA1 and obtain definitive in vivo evidence for its physiopathological significance. In aim 4 we will define the signaling function of collagen-bound VWF leading to platelet activation. We have characterized distinct intracytoplasmic Ca++ signals that follow platelet adhesion to immobilized VWFA1 or collagen under flow conditions, and found that they are enhanced when platelets interact with collagen-bound VWF. We propose to dissect the mechanisms of platelet activation supported by the collagen-VWF complex and the effects of hydrodynamic force on the process. The results of this research will improve our ability to influence disease processes that involve platelets in atherothrombosis.
在本申请中,我们建议继续努力,旨在阐明血管性血友病因子(VWF)的结构 以四个目标为核心的功能。在目的1中,我们将测试VWF A1结构域中的结构元件是否是 (VWFA 1)可以差异化地调节特定的粘合剂性质。初步数据显示, 糖蛋白(GP)Iba与固定在表面上的VWFA 1结合,导致血小板粘附, 通过与介导血小板聚集的可溶性VWF的结合相比不同的机制。我们 目的是确定特异性VWF启动和调节的独特结构元件 活性并在血管损伤模型中建立其功能相关性。在目标2中,我们打算确定 α-凝血酶是否可以作为VWF粘附特性的生理调节剂。我们假设 VWFA 1和α-凝血酶在与相同的GPIba受体结合时建立分子间接触,并且这 可能独立于剪切应力影响VWFA 1-GPIba键的稳定性。我们建议确定 支持与GPIba结合的α-凝血酶相互作用的VWFA 1残基,因此定义了一种新的 血栓形成过程中VWF功能的调节机制。在目标3中,我们建议评估 在人群中发现的特异性IgG是否是VWF活性的调节剂。我们已经确定, 人和小鼠血液中特异性IgG可选择性结合VWFA 1,并获得初步证据 这种IgG可能在血栓形成中起作用。我们的目标是描述特定的 IgG,定义与VWFA 1相互作用的模式,并获得其生理病理学的明确体内证据 意义在目标4中,我们将定义胶原结合的VWF的信号传导功能, 血小板活化我们已经描述了血小板粘附后胞浆内Ca++信号的特征 流动条件下固定的VWFA 1或胶原蛋白,并发现当血小板 与胶原结合VWF相互作用。我们建议剖析血小板活化的机制, 胶原蛋白-VWF复合物和流体动力对该过程的影响。的结果 研究将提高我们影响动脉粥样硬化血栓形成中涉及血小板的疾病过程的能力。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
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Zaverio M Ruggeri其他文献

Pathogen Reduced Cryoprecipitated Fibrinogen Complex (IFC) and Cryoprecipitated AHF Contain Von Willebrand Factor with Comparable Binding to Collagen and Support Shear-Induced Platelet Thrombus Formation
  • DOI:
    10.1182/blood-2023-187124
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Subramanian Yegneswaran;Alessandro Zarpellon;Jennifer N Orje;Michelle Gatmaitan;Nina Mufti;Laurence Corash;Zaverio M Ruggeri
  • 通讯作者:
    Zaverio M Ruggeri
Neutrophils release brakes of coagulation
中性粒细胞释放凝血的抑制物
  • DOI:
    10.1038/nm0810-851
  • 发表时间:
    2010-08-01
  • 期刊:
  • 影响因子:
    50.000
  • 作者:
    Wolfram Ruf;Zaverio M Ruggeri
  • 通讯作者:
    Zaverio M Ruggeri

Zaverio M Ruggeri的其他文献

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{{ truncateString('Zaverio M Ruggeri', 18)}}的其他基金

Glycoprotein Ib in vascular biology and host defense
糖蛋白 Ib 在血管生物学和宿主防御中的作用
  • 批准号:
    9384693
  • 财政年份:
    2017
  • 资助金额:
    $ 53.67万
  • 项目类别:
Platelet and coagulation activation in response to vascular injury
响应血管损伤的血小板和凝血激活
  • 批准号:
    9198882
  • 财政年份:
    2014
  • 资助金额:
    $ 53.67万
  • 项目类别:
Platelet and coagulation activation in response to vascular injury
响应血管损伤的血小板和凝血激活
  • 批准号:
    8976235
  • 财政年份:
    2014
  • 资助金额:
    $ 53.67万
  • 项目类别:
Role of Von Willebrand Factor in Platelet Thrombosis Formation
血管性血友病因子在血小板血栓形成中的作用
  • 批准号:
    8256550
  • 财政年份:
    2011
  • 资助金额:
    $ 53.67万
  • 项目类别:
Role of von Willebrand Factor in Platelet Thrombus Formation
血管性血友病因子在血小板血栓形成中的作用
  • 批准号:
    7768171
  • 财政年份:
    2009
  • 资助金额:
    $ 53.67万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    7029351
  • 财政年份:
    2005
  • 资助金额:
    $ 53.67万
  • 项目类别:
Ex Vivo and In Vivo Models of Hemostasis and Thrombosis Core
止血和血栓核心的体外和体内模型
  • 批准号:
    7029350
  • 财政年份:
    2005
  • 资助金额:
    $ 53.67万
  • 项目类别:
Platelet Interactions with Vessel Wall Components
血小板与血管壁成分的相互作用
  • 批准号:
    7029340
  • 财政年份:
    2005
  • 资助金额:
    $ 53.67万
  • 项目类别:
Initiation and Regulation of Platelet Thrombus Formation
血小板血栓形成的引发和调节
  • 批准号:
    6968162
  • 财政年份:
    2004
  • 资助金额:
    $ 53.67万
  • 项目类别:
Platelet interactions with vessel wall components
血小板与血管壁成分的相互作用
  • 批准号:
    6852337
  • 财政年份:
    2004
  • 资助金额:
    $ 53.67万
  • 项目类别:

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