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
• 负责人: Jeffrey D Esko
• 金额: $ 47.34万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10171430
• 关键词: 3-Dimensional; Address; Affect; Beds; Biology; Blood Coagulation Disorders; Blood Vessels; Brain; Cardiac; Cell surface; Cells; Clinical; Coagulation Process; Core Facility; Data; Disease; Endothelial Cells; Endothelium; Extravasation; Glycobiology; Glycocalyx; Glycoproteins; Goals; Grant; Heart; Hemolysin; Heparin; Heparin Lyase; Heparitin Sulfate; Host Defense; Human; Hyaluronan; Hypersensitivity; Immune response; Infection; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Intoxication; Literature; Liver; Lung; Mediating; Metabolism; Methods; Monitor; Mus; Mutation; Organ; Outcome; Pathogenicity; Pathologic; Patients; Plasma; Play; Predisposition; Prognostic Marker; Protein Glycosylation; Proteoglycan; Proteome; Proteomics; Publishing; Research; Resolution; Role; Sampling; Sepsis; Severities; Spleen; Staphylococcus aureus; Testing; Time; Tissues; Vascular Diseases; Vascular Endothelium; Vascular remodeling; Virulence Factors; diagnostic biomarker; in vivo; methicillin resistant Staphylococcus aureus; mortality; mouse model; novel marker; pathogen; pathogenic bacteria; programs; response; septic patients

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的目的介绍了整个程序的中心假设：蛋白质糖基化和 糖蛋白重塑改变败血症的凝血病和炎症。项目3将调查改建 由败血症诱导的血管糖脂以及这些变化如何影响小鼠的宿主反应和存活。 拟议的研究参与了该计划的所有核心设施，并借鉴了合并的专业知识 项目领导者和败血症，炎症生物学，凝结，蛋白质组学领域的领导者和核心领导者 和糖生物学。从最近的文献和初步数据来看，众所周知，败血症会引起变化 血浆糖蛋白的组成和血管内皮糖蛋白的脱落，导致血管 功能障碍和高死亡率。但是，几乎没有有关血管组成的信息 蛋白质组和糖蛋白酶及其对不同传染剂的响应方式的变化。在最后的赠款中 循环，我们开发了一种体内标记方法，该方法允许评估不同的血管蛋白质组 器官。我们表明，耐甲氧西林的金黄色葡萄球菌感染（MR）导致重塑 具有器官特异性的血管蛋白质组，导致发现蛋白聚糖4及其因素 调节透明质酸代谢为潜在的新型感染标志物。我们还表明硫酸乙酰肝素 由血管内皮产生的 在老鼠中。在肝脏中，硫酸乙酰肝素内皮硫酸盐的硫酸盐可预防炎症反应 MR诱导的凝血病。但是，在心脏中，发生病理变化，与 对金黄色葡萄球菌α-溶血素的超敏反应，这是一种关键的毒力因子。在下一个周期中，我们将 将体内标记方法扩展到包括其他常见的细菌病原体，这些病原体在人类中引起败血症 为了识别手术性致病机制，并确定是否可以通过反应对败血症进行分层 引起不同病原体的血管壁。我们将检查乙par硫酸盐调节的机制 alpha-Hemolysin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 败血症的一般标志，如果这些因素发挥了保护作用。我们还表明蛋白聚糖4和 透明质酸积聚在败血症患者的人血浆样品中。我们将关联这些标记 借助有关患者的临床信息，以确定这些标记是否分层败血症以及它们是否具有 作为诊断或预后标记的价值。总体目标是了解感染引起的重塑是否 血管糖蛋白酶的含量为识别疾病机制和一种对败血症进行分层的方式提供了一个窗口 跨时间，不同的传染性药物以及疾病解决过程。