Project 3: Heparan Sulfate Proteoglycans in the Pathogenesis of Sepsis
Project 3: Heparan Sulfate Proteoglycans in the Pathogenesis of Sepsis
批准号:
9072755
负责人:
Jeffrey D Esko
金额:
$54.16万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-15 至 2021-04-30
关键词:
AddressAffectAnimalsBindingBinding ProteinsBiologicalBiologyBiomedical ResearchBloodBlood CirculationBlood Coagulation DisordersBlood VesselsBlood coagulationBone Marrow TransplantationCessation of lifeCoagulation ProcessCore FacilityDataDisease ProgressionDropoutEndothelial CellsEscherichia coliEscherichia coli InfectionsExtravasationGap JunctionsGlycobiologyGlycoproteinsGlypicanHematologyHeparan Sulfate ProteoglycanHeparitin SulfateHomeostasisHumanImmune responseInfectionInflammationInflammatoryInflammatory ResponseInjuryKnock-outKnowledgeLethal Dose 50LeukocytesLiteratureMatrix Metalloproteinase InhibitorMeasuresMedicalMetalloproteasesMorbidity - disease rateMusMutationN-acetylglucosamine deacetylaseOnset of illnessOrganOutcomePathogenesisPathologyPatientsPlasmaPlasma ProteinsPlayPredispositionProtein GlycosylationProteinsProteomicsResearchResearch Project GrantsResearch ProposalsResourcesRoleSalmonella entericaSepsisSepsis SyndromeSeveritiesSourceStreptococcus pneumoniaeStructureSyndromeSystemTestingTissuesVascular Endothelial CellVascular EndotheliumWild Type Mousedisabilityfibroglycaninflammatory markerinhibitor/antagonistmicrobialmigrationmortalitymouse modelmutantnovel strategiespathogenpotential biomarkerpreventprogramsprotein complexproteoglycan core proteinresearch studysulfotransferasesyndecansyndecan-4
中文摘要
总结
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
UCSD Biomedical Scientist Career Development Program in Glycoscience
-
批准号:10439513
-
项目类别:
-
资助金额:$105.05万
-
财政年份:2018
-
负责人:Jeffrey D Esko
-
依托单位:
Glycosylation of the perineuronal net in Alzheimer's Disease
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批准号:9785861
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项目类别:
-
资助金额:$46.0万
-
财政年份:2018
-
负责人:Jeffrey D Esko
-
依托单位:
UCSD Biomedical Scientist Career Development Program in Glycoscience
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批准号:10197205
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项目类别:
-
资助金额:$105.5万
-
财政年份:2018
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负责人:Jeffrey D Esko
-
依托单位:
PROJECT 3 - Infection-Induced Remodeling of the Vascular Proteome
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批准号:10171430
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项目类别:
-
资助金额:$47.34万
-
财政年份:2016
-
负责人:Jeffrey D Esko
-
依托单位:
PROJECT 3 - Infection-Induced Remodeling of the Vascular Proteome
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批准号:10641853
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项目类别:
-
资助金额:$46.34万
-
财政年份:2016
-
负责人:Jeffrey D Esko
-
依托单位:
PROJECT 3 - Infection-Induced Remodeling of the Vascular Proteome
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批准号:10475614
-
项目类别:
-
资助金额:$46.34万
-
财政年份:2016
-
负责人:Jeffrey D Esko
-
依托单位:
Genome-wide Analysis of Heparan Sulfate using CRISPR/Cas9
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批准号:9103016
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项目类别:
-
资助金额:$16.86万
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财政年份:2015
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负责人:Jeffrey D Esko
-
依托单位:
Drug Discovery for Multiple Hereditary Exostoses
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批准号:8912269
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项目类别:
-
资助金额:$39.79万
-
财政年份:2013
-
负责人:Jeffrey D Esko
-
依托单位:
Drug Discovery for Multiple Hereditary Exostoses
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批准号:8735612
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项目类别:
-
资助金额:$37.7万
-
财政年份:2013
-
负责人:Jeffrey D Esko
-
依托单位:
Drug Discovery for Multiple Hereditary Exostoses
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批准号:8630072
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项目类别:
-
资助金额:$44.34万
-
财政年份:2013
-
负责人:Jeffrey D Esko
-
依托单位:
Drug Discovery for Multiple Hereditary Exostoses
-
批准号:9335653
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项目类别:
-
资助金额:$34.53万
-
财政年份:2013
-
负责人:Jeffrey D Esko
-
依托单位:
Drug Discovery for Multiple Hereditary Exostoses
-
批准号:9120805
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项目类别:
-
资助金额:$29.21万
-
财政年份:2013
-
负责人:Jeffrey D Esko
-
依托单位:
Drug Discovery for Multiple Hereditary Exostoses
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批准号:9283197
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项目类别:
-
资助金额:$5.32万
-
财政年份:2013
-
负责人:Jeffrey D Esko
-
依托单位:
Mechanisms of Prion Aggregation
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批准号:10407462
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项目类别:
-
资助金额:$50.16万
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财政年份:2011
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负责人:Jeffrey D Esko
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依托单位:
Mechanisms of Prion Aggregation
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批准号:10626014
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项目类别:
-
资助金额:$48.07万
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财政年份:2011
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负责人:Jeffrey D Esko
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依托单位:
Gene Discovery and Heparan Sulfate Biogenesis
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批准号:8035999
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项目类别:
-
资助金额:$19.31万
-
财政年份:2010
-
负责人:Jeffrey D Esko
-
依托单位:
Structure and Function of 3-O-sulfation in Heparan Sulfate
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批准号:8463564
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项目类别:
-
资助金额:$27.06万
-
财政年份:2010
-
负责人:Jeffrey D Esko
-
依托单位:
Structure and Function of 3-O-sulfation in Heparan Sulfate
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批准号:8260852
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项目类别:
-
资助金额:$29.46万
-
财政年份:2010
-
负责人:Jeffrey D Esko
-
依托单位:
Structure and Function of 3-O-sulfation in Heparan Sulfate
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批准号:7863947
-
项目类别:
-
资助金额:$33.37万
-
财政年份:2010
-
负责人:Jeffrey D Esko
-
依托单位:
Gene Discovery and Heparan Sulfate Biogenesis
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批准号:7772485
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项目类别:
-
资助金额:$23.79万
-
财政年份:2010
-
负责人:Jeffrey D Esko
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依托单位:
海外基金