PROJECT 3 - Infection-Induced Remodeling of the Vascular Proteome

项目 3 - 感染诱导的血管蛋白质组重塑

基本信息

项目摘要

Project Summary, UC San Diego, Project 3 The aims of Project 3 address the central hypothesis of the overall program: Protein glycosylation and glycoprotein remodeling alter the coagulopathy and inflammation of sepsis. Project 3 will investigate remodeling of the vascular glycocalyx induced by sepsis and how these changes affect host response and survival in mice. The proposed research engages all of the core facilities of the program and draws on the combined expertise of the Project Leaders and Core Leaders in infection and sepsis, inflammatory biology, coagulation, proteomics and glycobiology. From recent literature and preliminary data, it is well known that sepsis induces changes in the composition of plasma glycoproteins and shedding of the vascular endothelial glycocalyx, leading to vascular dysfunction and high mortality. However, little information is available about the composition of the vascular proteome and glycoproteome and how it changes in response to different infectious agents. Over the last grant cycle, we developed an in vivo tagging method that allows assessment of the vascular proteome in different organs. We showed that infection by methicillin-resistant Staphylococcus aureus (MR) results in remodeling of the vascular proteome in an organ-specific manner, leading to the discovery of proteoglycan 4 and factors that modulate hyaluronan metabolism as potential novel markers of infection. We also showed that heparan sulfate produced by the vascular endothelium plays an important role in determining the severity and outcome of sepsis in mice. In the liver, undersulfation of endothelial heparan sulfate protects against the inflammatory response and coagulopathy induced by MR. However, in the heart, pathological changes take place that correlate with hypersensitivity to Staphylococcus aureus alpha-hemolysin, a key virulence factor. In the next cycle, we will expand the in vivo tagging method to include other common bacterial pathogens that cause sepsis in humans in order to identify operative pathogenic mechanisms and to determine if sepsis can be stratified by responses in the vascular wall to different pathogens. We will examine the mechanism by which heparan sulfate modulates alpha-hemolysin sensitivity. We will determine if the induction of proteoglycan 4 and hyaluronan metabolism are general hallmarks of sepsis and if these factors serve a protective role. We also showed that proteoglycan 4 and hyaluronan accumulate in human plasma samples from patients with sepsis. We will correlate these markers with clinical information about the patients to determine if these markers stratify sepsis and whether they have value as diagnostic or prognostic markers. The overarching goal is to understand if infection-induced remodeling of the vascular glycoproteome provides a window to identify disease mechanisms and a way to stratify sepsis across time, different infectious agents, and during disease resolution.
项目摘要,加州大学圣地亚哥分校,项目3 项目3的目标是解决整个项目的中心假设:蛋白质糖基化和 糖蛋白重塑改变脓毒症的凝血病和炎症。项目3将调查重塑 脓毒症诱导的血管糖萼的变化以及这些变化如何影响小鼠的宿主反应和存活。 拟议的研究涉及该计划的所有核心设施,并借鉴了 感染和败血症、炎症生物学、凝血、蛋白质组学的项目负责人和核心负责人 和糖生物学从最近的文献和初步数据,众所周知,脓毒症引起的变化, 血浆糖蛋白的组成和血管内皮糖萼的脱落,导致血管 功能障碍和高死亡率。然而,关于血管的组成的信息很少。 蛋白质组和糖蛋白质组以及它如何响应不同的感染因子而变化。在上一次拨款中 循环中,我们开发了一种体内标记方法,可以评估不同血管蛋白质组中的血管蛋白质组。 机关我们发现,耐甲氧西林金黄色葡萄球菌(MR)感染可导致 以器官特异性方式研究血管蛋白质组,导致发现蛋白聚糖4和因子, 调节透明质酸代谢作为潜在的新的感染标志物。我们还发现硫酸乙酰肝素 血管内皮产生的蛋白质在决定脓毒症的严重程度和结果方面发挥着重要作用 对小鼠在肝脏中,内皮硫酸乙酰肝素的硫酸化不足可防止炎症反应 然而,在心脏中,病理变化发生与MR诱发的凝血病相关。 对金黄色葡萄球菌α-溶血素(一种关键毒力因子)过敏。在下一个周期,我们将 将体内标记方法扩展到包括在人类中引起败血症的其他常见细菌病原体, 为了确定有效的致病机制,并确定脓毒症是否可以分层的反应, 不同病原体的血管壁。我们将研究硫酸乙酰肝素调节 α-溶血素敏感性我们将确定蛋白聚糖4和透明质酸代谢的诱导是否是 脓毒症的一般标志以及这些因素是否起保护作用。我们还发现蛋白聚糖4和 透明质酸在脓毒症患者人血浆样品中积累。我们会把这些标记 与患者的临床信息,以确定这些标志物是否分层败血症, 作为诊断或预后标志物的价值。首要目标是了解感染引起的重塑 血管糖蛋白质组的研究为确定疾病机制和脓毒症分层提供了一个窗口 在不同的时间、不同的传染源和疾病消退期间。

项目成果

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Jeffrey D Esko其他文献

Jeffrey D Esko的其他文献

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{{ truncateString('Jeffrey D Esko', 18)}}的其他基金

UCSD Biomedical Scientist Career Development Program in Glycoscience
加州大学圣地亚哥分校糖科学生物医学科学家职业发展计划
  • 批准号:
    10439513
  • 财政年份:
    2018
  • 资助金额:
    $ 46.34万
  • 项目类别:
Glycosylation of the perineuronal net in Alzheimer's Disease
阿尔茨海默病中神经周围网络的糖基化
  • 批准号:
    9785861
  • 财政年份:
    2018
  • 资助金额:
    $ 46.34万
  • 项目类别:
UCSD Biomedical Scientist Career Development Program in Glycoscience
加州大学圣地亚哥分校糖科学生物医学科学家职业发展计划
  • 批准号:
    10197205
  • 财政年份:
    2018
  • 资助金额:
    $ 46.34万
  • 项目类别:
PROJECT 3 - Infection-Induced Remodeling of the Vascular Proteome
项目 3 - 感染诱导的血管蛋白质组重塑
  • 批准号:
    10171430
  • 财政年份:
    2016
  • 资助金额:
    $ 46.34万
  • 项目类别:
Project 3: Heparan Sulfate Proteoglycans in the Pathogenesis of Sepsis
项目3:硫酸乙酰肝素蛋白多糖在脓毒症发病机制中的作用
  • 批准号:
    9072755
  • 财政年份:
    2016
  • 资助金额:
    $ 46.34万
  • 项目类别:
PROJECT 3 - Infection-Induced Remodeling of the Vascular Proteome
项目 3 - 感染诱导的血管蛋白质组重塑
  • 批准号:
    10475614
  • 财政年份:
    2016
  • 资助金额:
    $ 46.34万
  • 项目类别:
Genome-wide Analysis of Heparan Sulfate using CRISPR/Cas9
使用 CRISPR/Cas9 对硫酸乙酰肝素进行全基因组分析
  • 批准号:
    9103016
  • 财政年份:
    2015
  • 资助金额:
    $ 46.34万
  • 项目类别:
Drug Discovery for Multiple Hereditary Exostoses
多种遗传性外生骨疣的药物发现
  • 批准号:
    8912269
  • 财政年份:
    2013
  • 资助金额:
    $ 46.34万
  • 项目类别:
Drug Discovery for Multiple Hereditary Exostoses
多种遗传性外生骨疣的药物发现
  • 批准号:
    8735612
  • 财政年份:
    2013
  • 资助金额:
    $ 46.34万
  • 项目类别:
Drug Discovery for Multiple Hereditary Exostoses
多种遗传性外生骨疣的药物发现
  • 批准号:
    8630072
  • 财政年份:
    2013
  • 资助金额:
    $ 46.34万
  • 项目类别:

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