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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

基本信息

批准号：
9072755
负责人：
Jeffrey D Esko
金额：
$ 54.16万
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 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9072755
关键词：
Address Affect Animals Binding Binding Proteins Biological Biology Biomedical Research Blood Blood Circulation Blood Coagulation Disorders Blood Vessels Blood coagulation Bone Marrow Transplantation Cessation of life Coagulation Process Core Facility Data Disease Progression Dropout Endothelial Cells Escherichia coli Escherichia coli Infections Extravasation Gap Junctions Glycobiology Glycoproteins Glypican Hematology Heparan Sulfate Proteoglycan Heparitin Sulfate Homeostasis Human Immune response Infection Inflammation Inflammatory Inflammatory Response Injury Knock-out Knowledge Lethal Dose 50 Leukocytes Literature Matrix Metalloproteinase Inhibitor Measures Medical Metalloproteases Morbidity - disease rate Mus Mutation N-acetylglucosamine deacetylase Onset of illness Organ Outcome Pathogenesis Pathology Patients Plasma Plasma Proteins Play Predisposition Protein Glycosylation Proteins Proteomics Research Research Project Grants Research Proposals Resources Role Salmonella enterica Sepsis Sepsis Syndrome Severities Source Streptococcus pneumoniae Structure Syndrome System Testing Tissues Vascular Endothelial Cell Vascular Endothelium Wild Type Mouse disability fibroglycan inflammatory marker inhibitor/antagonist microbial migration mortality mouse model mutant novel strategies pathogen potential biomarker prevent programs protein complex proteoglycan core protein research study sulfotransferase syndecan syndecan-4

项目摘要

SUMMARY The aims of this project address the central hypothesis of the overall program, that Protein glycosylation and glycoprotein remodeling modulate the coagulopathy and inflammation of sepsis. This research project will investigate the roles of heparan sulfate (HS), heparan sulfate proteoglycans (HSPGs), and matrix metalloproteases (MMPs) in the coagulopathy and inflammation of sepsis. 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, coagulopathy, proteomics, and glycobiology. From recent literature and preliminary data, HS attached to endothelial HSPGs alters the outcome of sepsis coincident with HSPG shedding from vascular endothelial cells induced by MMPs. Moreover, vascular HS deficiency has opposing effects on the outcomes of sepsis caused by different microbial pathogens including Gram-positive Streptococcus pneumoniae (SPN) and Gram-negative Salmonella enterica Typhimurium (ST). In addition, MMP inhibition affects HSPG shedding and provides a protective role in the pathogenesis of sepsis caused by ST. These findings infer the possibility that the pathogenesis of sepsis may be stratified by different host responses in the context of distinct pathogens. Research proposed in Project 3 will further test the hypothesis that the major HSPGs expressed on the vascular endothelium, namely syndecan-1, syndecan-2, syndecan-4, and glypican-1, compose a functional nexus with MMPs that confer separate outcomes in the coagulopathy and inflammation of sepsis caused by these bacterial pathogens and Gram-negative Escherichia coli (EC). This project will also generate unique knowledge about the repertoire of HSPG-protein complexes in disease onset and progression. The proposed studies will focus on HSPGs and HS-binding proteins in mice and humans during sepsis caused by Gram-negative and Gram-positive pathogens, and in Systemic Inflammatory Response Syndrome (SIRS) and may yield new potential biomarkers and novel approaches to modulating the outcomes of sepsis and SIRS. The interdisciplinary expertise of the Project Leaders and Core Leaders, and the combined resources available, will achieve a mechanistic understanding of HSPG homeostasis and HSPG-protein complex determinants implicated in modulating the coagulation, coagulopathy, inflammation, and outcomes of SIRS and sepsis due to infections involving different pathogens.

总结