FXI and Sepsis
FXI and Sepsis
批准号:
9127988
负责人:
FLOREA LUPU
金额:
$44.77万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-09-01 至 2019-06-30
关键词:
AcuteAffectAfibrinogenemiaAnimal ModelAntibodiesAnticoagulationBlood Coagulation DisordersBlood Coagulation FactorBlood Coagulation Factor VIIBlood PlateletsBlood VesselsBlood coagulationCardiopulmonaryCardiovascular systemCessation of lifeClinical TrialsCoagulation ProcessConsumptionDevelopmentDiseaseDisease OutcomeDisseminated Intravascular CoagulationEdemaEndothelial CellsEventF2R geneFactor XIIFactor XIIaFailureFibrinFunctional disorderGenerationsGoalsHealthHemorrhageHemostatic AgentsHemostatic functionHospital MortalityHourHumanHypotensionImmune responseIn VitroInfectionInflammationInflammatory ResponseInjuryLeadLeftLife Cycle StagesListeriosisMedicalModelingMolecularMolecular TargetMusNatural ImmunityOrganOutcomePathogenesisPathologicPathway interactionsPatient-Focused OutcomesPatientsPeptidoglycanPerfusionPeritonitisPlatelet ActivationPlayPolyphosphatesPrimatesResearchResearch Project GrantsRoleSepsisSeriesSignal TransductionStrokeSurfaceSyndromeTestingTherapeuticThrombinThrombosisThrombusTissuesTranslatingTranslationsVascular DiseasesVasodilationVenous ThrombosisVirulenceYersiniaactivated Protein Ccombatdesigndrotrecogin alfaeffective therapyendothelial dysfunctionimprovedin vivoinhibitor/antagonistmortalitynovelnovel therapeuticsoutcome forecastpathogenpatient subsetspreventresearch studyseptic
中文摘要
英文摘要
DESCRIPTION (provided by applicant): Our research project is designed to test our central hypothesis that activation of the contact factor pathway contributes to pathologic mechanisms that lead to vascular dysfunction, thrombin generation, and inflammatory responses during sepsis induced by specific infectious pathogens. Sepsis is a sequel of molecular and cellular events that perpetually change over the course of this life threatening disease condition. Failure of vasoregulation, poor tissue perfusion, edema, and systemic hypotension are hallmarks of severe sepsis, and, by triggering a cardiopulmonary and vascular collapse, leads to death when left untreated. Severe sepsis may be accompanied by disseminated intravascular coagulation (DIC) that aggravates the vasodilation and edema-associated tissue perfusion insufficiency. DIC can lead to the failure of hemostasis, and subsequent bleeding due to the consumption of coagulation factors and platelets. We focus on the contact activation pathway, because 1) there appears to be a causal relationship between pathological activation of the coagulation factor XII and the poor prognosis of some forms of sepsis, and 2) targeting the contact activation pathway as a therapeutic approach is unlikely to have detrimental consequences for the host. We will define the role of the molecular steps in the contact pathway of coagulation in the development and outcomes of severe sepsis. We will define the roles of FXII (Aim 1) and its procoagulant substrate FXI (Aim 2), and will translate our mechanistic in vitro and ex vivo studies to define th pathological role of activation of the contact pathway in 2 distinct primate models of severe sepsis. The potential translational relevance of our project will be the identification of safe and
druggable molecular targets and mechanisms within the contact activation pathway. Our research may ultimately provide rationale for the development of selective contact activation pathway inhibitors that could benefit sepsis patients infected with pathogens that exploit the contact activation pathway for virulence. Importantly, this approach would not do harm to patients whose infection is controlled by endogenous extrinsic pathway-dependent fibrin formation as part of the innate immune response.
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会议论文
Complement C5 inhibition as sepsis therapy
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批准号:10569623
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项目类别:
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资助金额:$63.34万
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财政年份:2022
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负责人:FLOREA LUPU
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依托单位:
Complement C5 inhibition as sepsis therapy
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批准号:10420351
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项目类别:
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资助金额:$63.34万
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财政年份:2022
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负责人:FLOREA LUPU
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依托单位:
Discovery and Characterization of Novel Sepsis Proteome Biomarkers
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批准号:10364288
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项目类别:
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资助金额:$55.43万
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财政年份:2021
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负责人:FLOREA LUPU
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依托单位:
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批准号:10676088
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项目类别:
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资助金额:$55.31万
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财政年份:2020
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负责人:FLOREA LUPU
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依托单位:
Contact Activation and Infection
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批准号:10458712
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项目类别:
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资助金额:$79.04万
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财政年份:2020
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负责人:FLOREA LUPU
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依托单位:
Contact Activation and Infection
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批准号:10269038
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项目类别:
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资助金额:$52.6万
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财政年份:2020
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负责人:FLOREA LUPU
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依托单位:
MICROSCOPY
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批准号:8364980
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项目类别:
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资助金额:$20.05万
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财政年份:2011
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负责人:FLOREA LUPU
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依托单位:
COBRE: OK MED RES FOUND: CORE I: IN VITRO MICROSCOPY CORE
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批准号:8168454
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项目类别:
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资助金额:$13.0万
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财政年份:2010
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负责人:FLOREA LUPU
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依托单位:
Intravital Multiphoton Microscope
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批准号:7794743
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项目类别:
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资助金额:$50.0万
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财政年份:2010
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负责人:FLOREA LUPU
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依托单位:
EPCR, TAFI as Regulators of PMN/Endothelial Interaction
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批准号:7939125
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项目类别:
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资助金额:$9.25万
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财政年份:2009
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负责人:FLOREA LUPU
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依托单位:
COBRE: OK MED RES FOUND: CORE I: IN VITRO MICROSCOPY CORE
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批准号:7610582
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项目类别:
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资助金额:$10.05万
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财政年份:2007
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负责人:FLOREA LUPU
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依托单位:
COBRE: OK MED RES FOUND: CORE I: IN VITRO MICROSCOPY CORE
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批准号:7382049
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项目类别:
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资助金额:$10.55万
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财政年份:2006
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负责人:FLOREA LUPU
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依托单位:
Animal Model Core
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批准号:9927972
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项目类别:
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资助金额:$59.37万
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财政年份:2004
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负责人:FLOREA LUPU
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依托单位:
Animal Model Core
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批准号:10237855
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项目类别:
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资助金额:$59.17万
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财政年份:2004
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负责人:FLOREA LUPU
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依托单位:
CORE--IN VITRO MICROSCOPY
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批准号:6981939
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项目类别:
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资助金额:$9.64万
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财政年份:2004
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负责人:FLOREA LUPU
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依托单位:
EPCR, TAFI as Regulators of PMN/Endothelial Interaction
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批准号:6948623
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项目类别:
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资助金额:$31.79万
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财政年份:1986
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负责人:FLOREA LUPU
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依托单位:
EPCR, TAFI as Regulators of PMN/Endothelial Interaction
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批准号:7275453
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项目类别:
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资助金额:$31.96万
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财政年份:1986
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负责人:FLOREA LUPU
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依托单位:
EPCR, TAFI as Regulators of PMN/Endothelial Interaction
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批准号:6819114
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项目类别:
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资助金额:$30.86万
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财政年份:1986
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负责人:FLOREA LUPU
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依托单位:
EPCR, TAFI as Regulators of PMN/Endothelial Interaction
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批准号:7114825
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项目类别:
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资助金额:$31.96万
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财政年份:1986
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负责人:FLOREA LUPU
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依托单位:
Microscopy Core
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批准号:9315856
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项目类别:
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资助金额:$44.38万
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财政年份:--
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负责人:FLOREA LUPU
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依托单位:
海外基金