Activation of encrypted tissue factor during thrombus formation in vivo

体内血栓形成过程中加密组织因子的激活

基本信息

  • 批准号:
    8268395
  • 负责人:
  • 金额:
    $ 12.46万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-09-22 至 2013-12-31
  • 项目状态:
    已结题

项目摘要

As a mechanism of host defense, the initiation of the blood coagulation cascade requires tight regulation both in its timing and location. Major causes of death, including stroke, heart attack and pulmonary embolism, are each linked to pathologic thrombosis. Current teaching of coagulation has evolved from in vitro studies in which isolated components of this complex system are studied individually. My long-term goal is to elucidate the mechanism initiating coagulation in vivo and to determine how this critical step is regulated. Recently developed imaging technologies allow for the study of protein interactions at the site of thrombus formation in a living animal in real time. Tissue factor (TF) is required to initiate bloodcoagulation, thrombin formation and fibrin generation. It has been dogma that tissue factor is shielded from the circulation and is only exposed by vascular injury. However, TF has been identified on circulating microparticles, as well as on leukocytes and endothelial cells. Recent studies have led to the novel proposal that oxidation of TF leads to disulfide bond formation, acting as a molecular switch that changes latent TF to a procoagulant form. We hypothesize that an encrypted form of TF exists within the circulation that is activated during thrombus formation and fibrin generation in vivo. This would be a novel mechanism of TF involvement in thrombosis. We base this hypothesis on the following observations: 1) in vivo evidence of circulating TF accumulating in a growing thrombus, 2) a discrepancy between circulating TF concentration as measured by antigen and function - circulating antigen far exceeds the amount required to initiate coagulation and 3) disruption of the Cys186-Cys209 disulfide bond in tissue factor decreases its procoagulant activity, and this is reversible by forming this same disulfide bond. Based on these observations, we will characterize active and encrypted tissue factor isoforms in vivo using intravital microscopy and isoform-specific antibodies. We will characterize known antibodies for isoform specificity and have developed novel antibodies using recombinant phage display technology. These antibodies will allow visualization of TF isoforms during laser-induced thrombus formation in a living mouse. Furthermore, mouse models deficient in TF in individual tissues of interest, including monocytes and endothelial cells, will be employed to investigate the role of these tissues in TF-mediated thrombus formation in vivo.
作为宿主防御机制,凝血级联的启动需要严格调节 无论是在时间上还是在地点上。死亡的主要原因包括中风、心脏病和肺结核 栓塞,均与病理性血栓形成有关。目前的凝血教学是从 体外研究,对这个复杂系统的分离成分进行单独研究。我的长期 目标是阐明体内凝血的启动机制并确定这一关键步骤是如何进行的 受监管。最近开发的成像技术可以研究蛋白质相互作用的位点 活体动物中实时血栓形成。组织因子(TF)是启动血液凝固所必需的, 凝血酶的形成和纤维蛋白的生成。人们一直认为组织因子不受 血液循环,仅因血管损伤而暴露。然而,TF 已在流通中被识别出 微粒以及白细胞和内皮细胞。最近的研究导致了小说 提出 TF 的氧化导致二硫键形成,充当改变的分子开关 潜在的 TF 转变为促凝血形式。我们假设流通中存在加密形式的 TF 在体内血栓形成和纤维蛋白生成过程中被激活。这将是一个新颖的机制 TF 参与血栓形成。我们的假设基于以下观察:1)体内 循环 TF 在不断增长的血栓中积累的证据,2) 循环 TF 之间的差异 通过抗原和功能测量的浓度 - 循环抗原远远超过了所需的量 启动凝血,3) 组织因子中 Cys186-Cys209 二硫键的破坏降低了其 促凝血活性,并且通过形成相同的二硫键,这是可逆的。基于这些 观察结果,我们将使用活体内技术表征活性和加密的组织因子亚型 显微镜检查和亚型特异性抗体。我们将表征已知抗体的异构体特异性 并利用重组噬菌体展示技术开发了新型抗体。这些抗体将 允许在活体小鼠中激光诱导血栓形成过程中可视化 TF 同工型。此外, 单个感兴趣组织(包括单核细胞和内皮细胞)缺乏 TF 的小鼠模型将 用于研究这些组织在 TF 介导的体内血栓形成中的作用。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Kaposiform lymphangiomatosis: a distinct aggressive lymphatic anomaly.
  • DOI:
    10.1016/j.jpeds.2013.10.013
  • 发表时间:
    2014-02
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Croteau SE;Kozakewich HP;Perez-Atayde AR;Fishman SJ;Alomari AI;Chaudry G;Mulliken JB;Trenor CC 3rd
  • 通讯作者:
    Trenor CC 3rd
Risk factors, morbidity, and treatment of thrombosis in children and young adults with active inflammatory bowel disease.
患有活动性炎症性肠病的儿童和年轻人血栓形成的危险因素、发病率和治疗。
  • DOI:
    10.1097/mpg.0b013e31829ce5cd
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    2.9
  • 作者:
    Zitomersky,NaamahL;Levine,AnneE;Atkinson,BenjaminJ;Harney,KathyM;Verhave,Menno;Bousvaros,Athos;Lightdale,JeniferR;Trenor3rd,CameronC
  • 通讯作者:
    Trenor3rd,CameronC
High incidence of catheter-associated venous thromboembolic events in patients with long gap esophageal atresia treated with the Foker process.
采用 Foker 手术治疗的长间隙食管闭锁患者中导管相关静脉血栓栓塞事件的发生率较高。
  • DOI:
    10.1016/j.jpedsurg.2013.09.003
  • 发表时间:
    2014
  • 期刊:
  • 影响因子:
    2.4
  • 作者:
    Bairdain,Sigrid;Kelly,DanielP;Tan,Corinne;Dodson,Brenda;Zurakowski,David;Zurakowksi,David;Jennings,RussellW;Trenor3rd,CameronC
  • 通讯作者:
    Trenor3rd,CameronC
Kaposiform hemangioendothelioma: atypical features and risks of Kasabach-Merritt phenomenon in 107 referrals.
  • DOI:
    10.1016/j.jpeds.2012.06.044
  • 发表时间:
    2013-01
  • 期刊:
  • 影响因子:
    5.1
  • 作者:
    Croteau, Stacy E.;Liang, Marilyn G.;Kozakewich, Harry P.;Alomari, Ahmad I.;Fishman, Steven J.;Mulliken, John B.;Trenor, Cameron C., III
  • 通讯作者:
    Trenor, Cameron C., III
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Cameron Trenor其他文献

Cameron Trenor的其他文献

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{{ truncateString('Cameron Trenor', 18)}}的其他基金

Activation of encrypted tissue factor during thrombus formation in vivo
体内血栓形成过程中加密组织因子的激活
  • 批准号:
    7532912
  • 财政年份:
    2008
  • 资助金额:
    $ 12.46万
  • 项目类别:
Activation of encrypted tissue factor during thrombus formation in vivo
体内血栓形成过程中加密组织因子的激活
  • 批准号:
    8070020
  • 财政年份:
    2008
  • 资助金额:
    $ 12.46万
  • 项目类别:
Activation of encrypted tissue factor during thrombus formation in vivo
体内血栓形成过程中加密组织因子的激活
  • 批准号:
    7689915
  • 财政年份:
    2008
  • 资助金额:
    $ 12.46万
  • 项目类别:
Activation of encrypted tissue factor during thrombus formation in vivo
体内血栓形成过程中加密组织因子的激活
  • 批准号:
    7849590
  • 财政年份:
    2008
  • 资助金额:
    $ 12.46万
  • 项目类别:

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