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.
项目总结,加州大学圣地亚哥分校,项目3

项目成果

期刊论文数量(0)
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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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