权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

批准号：
10641853
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
项目类别：
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/10641853
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 Staphylococcus aureus infection 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

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