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
• 负责人: Jeffrey D Esko
• 金额: $ 46.34万
• 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/10475614
• 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; antagonist; 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.

加州大学圣地亚哥分校项目摘要，项目3 项目3的目标解决了整个计划的中心假设：蛋白质糖基化和 糖蛋白重塑改变了脓毒症的凝血障碍和炎症反应。项目3将调查改建 以及这些变化如何影响宿主的反应和小鼠的存活。 拟议的研究涉及该方案的所有核心设施，并借鉴了 感染与败血症、炎症生物学、凝血、蛋白质组学方面的项目负责人和核心负责人 和糖生物学。根据最近的文献和初步数据，众所周知，脓毒症会导致 血浆糖蛋白的组成和血管内皮细胞的脱落导致血管生成 功能障碍和高死亡率。然而，关于血管成分的信息很少。 蛋白质组和糖蛋白质组以及它们如何对不同的感染源做出反应。在最后一次拨款上 周期中，我们开发了一种体内标记方法，可以评估不同组织中的血管蛋白质组 器官。我们发现，耐甲氧西林金黄色葡萄球菌(MR)感染导致血管重构。 血管蛋白质组以器官特异的方式，导致蛋白多糖4和因子的发现 调节透明质酸代谢作为潜在的感染新标记物。我们还发现硫酸乙酰肝素 由血管内皮细胞产生的物质在决定脓毒症的严重程度和预后方面起着重要作用 在老鼠身上。在肝脏中，内皮细胞硫酸肝素硫酸盐化不足可保护炎症反应。 然而，在心脏中，会发生与以下因素相关的病理变化 对金黄色葡萄球菌α-溶血素的超敏反应，这是一个关键的毒力因素。在下一个周期中，我们将 将体内标记方法扩展到包括其他导致人类脓毒症的常见细菌病原体 为了确定手术致病机制，并确定脓毒症是否可以根据反应分层。 不同病原体的血管壁。我们将研究硫酸乙酰肝素调节的机制 甲型溶血素敏感性。我们将确定蛋白多糖4和透明质酸代谢的诱导是否 脓毒症的一般特征以及这些因素是否起到保护作用。我们还证明了蛋白多糖4和 脓毒症患者的人血浆样本中积累了透明质酸。我们将把这些标记关联起来 根据患者的临床信息来确定这些标志物是否对脓毒症进行分层以及它们是否 作为诊断或预后标志的价值。最主要的目标是了解感染诱导的重塑 血管糖蛋白质组的研究为确定疾病机制和对脓毒症分层提供了一个窗口 在不同的时间、不同的感染源和疾病解决期间。