Contact Activation and Infection

接触激活和感染

基本信息

  • 批准号:
    10458712
  • 负责人:
  • 金额:
    $ 79.04万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-23 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

Project Summary Our research project is designed to test our central hypothesis that the contact activation system contributes to pathologic mechanisms that lead to vascular dysfunction, thrombin generation, and inflammatory responses during systemic bacterial challenge by specific pathogens. Despite the availability of effective antibiotics, sepsis remains a prevalent clinical syndrome and significant cause of severe in-hospital morbidity and mortality, brought about by a sequence of rapidly advancing dynamic molecular and cellular events that occur upon exposure to and subsequent systemic infection by certain pathogens. Complicating the problem is the increasing prevalence of multiresistant bacterial pathogens. At present, after more than half a century of research, drug development, and countless clinical trials, there are still no FDA-approved marketed drugs specifically indicated for the treatment of sepsis. Sepsis can lead to multiple organ system failure, including failure of vasoregulation, poor tissue perfusion, edema, and systemic hypotension, which are hallmarks of severe sepsis. By triggering cardiopulmonary and vascular collapse, it is often lethal even with available supportive and antibiotic treatments. Sepsis may be accompanied by disseminated intravascular coagulation (DIC), which can lead to both thrombosis and bleeding due to the consumptive coagulopathy. We focus on the contact activation system, because 1) there appears to be a causal relationship between activation of coagulation factor XII and the poor prognosis of some forms of sepsis, and 2) targeting the contact activation system as a therapeutic approach is unlikely to have detrimental consequences for the host such as bleeding. We will study the role of the molecular steps in the contact activation system in the development and outcome of experimental bacterial infection, in vivo. We will define the roles of FXII (Aim 1) and its procoagulant substrate FXI (Aim 2), and translate our mechanistic in vitro studies to characterize the pathological role of contact activation in two distinct baboon models of bacterial infection. The potential translational relevance of our project will be the identification of safe and druggable molecular targets and mechanisms within the contact activation system. Our research may ultimately provide rationale for the development of selective contact activation inhibitors that could safely benefit patients that have or are at risk of infections by pathogens that can cause contact system activation.
项目摘要 我们的研究项目旨在检验我们的中心假设,即接触激活系统 有助于导致血管功能障碍,凝血酶产生和 特定病原体在全身细菌挑战期间的炎症反应。 尽管有效抗生素可用,但败血症仍然是一种普遍的临床综合征和重要的 严重的院内发病率和死亡率,一系列快速前进带来 暴露于暴露于和随后的全身感染时发生的动态分子和细胞事件 某些病原体。使问题复杂化的是多耐药细菌的患病率增加 病原体。目前,经过半个多世纪的研究,药物开发和无数 临床试验,仍然没有专门用于治疗的FDA批准的销售药物 败血症。败血症会导致多器官系统故障,包括血管调节失败,组织不良 灌注,水肿和全身性低血压,这是严重败血症的标志。通过触发 心肺和血管塌陷,即使有可用的支持和抗生素,它也通常是致命的 治疗。败血症可能伴随着散布的血管内凝血(DIC) 由于消耗性凝血病而引起的血栓形成和出血。我们专注于接触激活 系统,因为1)凝结因子XII的激活之间似乎存在因果关系 以及某些形式的败血症的预后不良,以及2)将接触激活系统作为一个 治疗方法不太可能对宿主(例如出血)产生有害后果。我们将 研究分子步骤在接触激活系统中的作用 实验细菌感染,体内。我们将定义FXII(AIM 1)及其Procagulant的作用 底物FXI(AIM 2),并翻译我们的机械体外研究,以表征 两种不同的细菌感染模型中的接触激活。 我们项目的潜在翻译相关性将是确定安全和可毒品 接触激活系统中的分子靶标和机制。我们的研究最终可能 为开发可以安全受益的选择性接触激活抑制剂提供理由 病原体有或有可能引起接触系统激活的病原体感染的患者。

项目成果

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FLOREA LUPU其他文献

FLOREA LUPU的其他文献

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{{ truncateString('FLOREA LUPU', 18)}}的其他基金

Complement C5 inhibition as sepsis therapy
补体 C5 抑制作为脓毒症治疗
  • 批准号:
    10569623
  • 财政年份:
    2022
  • 资助金额:
    $ 79.04万
  • 项目类别:
Complement C5 inhibition as sepsis therapy
补体 C5 抑制作为脓毒症治疗
  • 批准号:
    10420351
  • 财政年份:
    2022
  • 资助金额:
    $ 79.04万
  • 项目类别:
Discovery and Characterization of Novel Sepsis Proteome Biomarkers
新型脓毒症蛋白质组生物标志物的发现和表征
  • 批准号:
    10364288
  • 财政年份:
    2021
  • 资助金额:
    $ 79.04万
  • 项目类别:
Contact Activation and Infection
接触激活和感染
  • 批准号:
    10676088
  • 财政年份:
    2020
  • 资助金额:
    $ 79.04万
  • 项目类别:
Contact Activation and Infection
接触激活和感染
  • 批准号:
    10269038
  • 财政年份:
    2020
  • 资助金额:
    $ 79.04万
  • 项目类别:
FXI and Sepsis
FXI 和败血症
  • 批准号:
    9127988
  • 财政年份:
    2015
  • 资助金额:
    $ 79.04万
  • 项目类别:
MICROSCOPY
显微镜
  • 批准号:
    8364980
  • 财政年份:
    2011
  • 资助金额:
    $ 79.04万
  • 项目类别:
COBRE: OK MED RES FOUND: CORE I: IN VITRO MICROSCOPY CORE
COBRE:确定医学研究成果:核心 I:体外显微镜核心
  • 批准号:
    8168454
  • 财政年份:
    2010
  • 资助金额:
    $ 79.04万
  • 项目类别:
Intravital Multiphoton Microscope
活体多光子显微镜
  • 批准号:
    7794743
  • 财政年份:
    2010
  • 资助金额:
    $ 79.04万
  • 项目类别:
EPCR, TAFI as Regulators of PMN/Endothelial Interaction
EPCR、TAFI 作为 PMN/内皮相互作用的调节剂
  • 批准号:
    7939125
  • 财政年份:
    2009
  • 资助金额:
    $ 79.04万
  • 项目类别:

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  • 批准号:
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  • 批准号:
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  • 财政年份:
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