PDl: Function in thrombus formation and antithrombotic action of inhibitors in m
PDl: Function in thrombus formation and antithrombotic action of inhibitors in m
批准号:
8401639
负责人:
Bruce Furie
金额:
$40.98万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-09-01 至 2017-04-30
关键词:
Active SitesAmino AcidsAntibodiesAntigensAntiphospholipid SyndromeBacitracinBindingBlood CirculationBlood Coagulation DisordersBlood PlateletsBlood VesselsCellsCessation of lifeCloningComplexCysteineDeep Vein ThrombosisDisulfidesEndoplasmic ReticulumEnzymesExtracellular ProteinFamilyFibrinFibrinolytic AgentsGenerationsGlycoproteinsHumanImageryIn VitroInfusion proceduresInjuryInstructionIntegrin beta3IntegrinsIsomeraseLasersLinkLocationMentorsMethodsModelingMonitorMonoclonal AntibodiesMusMyocardial InfarctionNatureNobel PrizeOxidoreductaseParalysedPerinatalPharmacologyPlatelet ActivationPlatelet aggregationPlayPropertyProtein BiosynthesisProtein C DeficiencyProtein Disulfide IsomeraseProteinsPulmonary EmbolismQuercetinRestRoentgen RaysRoleRutinShapesStrokeStructureSulfhydryl CompoundsSurfaceTFPITestingThioredoxinThromboembolismThromboplastinThrombosisThrombusTimeUnited StatesVenouscremaster muscledesigndisulfide bondfactor V Leidenfetalin vivoinhibitor/antagonistintravital fluorescence microscopyintravital microscopymortalitymouse modelmutantneonatal deathnovelpreventprototypeyeast protein
中文摘要
项目概述(见说明):
英文摘要
PROJECT SUMMARY (See instructions):
To determine whether extracellular PDl plays a role in thrombus formation, PDl expression, platelet accumulation, and fibrin generation were monitored in the blood vessels of mice following laser-induced arteriolar injury. A time-dependent increase in PDl antigen was observed in the thrombus following injury.
Infusion of bacitracin or a blocking monoclonal antibody to PDl into the circulation completely inhibited platelet thrombus formation and fibrin generation. These results indicate that PDl is required in vivo for both fibrin generation and platelet thrombus formation. The objective in this project is to determine whether inhibitors of PDl represent a new class of antithrombotic agents. In Aim #1, the current project proposes to Identify the substrates of PDl that participate in the initiation of thrombus formation by the expression of mutant forms of thiol isomerases into experimental thrombi ex vivo and the trapping of disulfide-linked complexes of thiol isomerases and their substrates. In Aim #2, the xray crystal structure of human PDl and PDl in complex will be determined. These structures will include PDl and PDl bound to an anfi-PDI Fab, PDl
complexed to quercetin 3-rutinoside and to quercetin, and PDl complexed to beta3 integrin. In Aim #3, antithrombotic properties of quercetin will be tested in mice. The pharmacology of quercetin as an antithrombotic agent will be initially studied by direct visualization of thrombus inhibifion using the laserinduced thrombus formation model in the cremaster muscle of the mouse using intravital microscopy. The inhibition of thrombosis-initiated fetal/neonatal demise by quercetin will be tested in two mouse models: perinatal thrombosis with homozygous Factor V Leiden and heterozygous TFPI deficiency, and consumptive coagulopathy with homozygous protein C deficiency. If quercetin is an active antithrombotic, we will determine whether quercetin, which inhibits both platelet aggregation and fibrin generation, is superior to standard antithrombotic agents. PDl inhibitors will be compared to conventional antithrombotic agents in
mouse models of thrombosis. These will include death or paralysis induced by pulmonary embolism, and by intravital study of thrombus formation associated with acquired anti-phospholipid syndrome.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Vascular Thiol Isomerases in Thrombosis
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批准号:9461119
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项目类别:
-
资助金额:$82.63万
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财政年份:2017
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负责人:Bruce Furie
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依托单位:
PDI inhibition to prevent thrombosis in humans
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批准号:8532976
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项目类别:
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资助金额:$54.39万
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财政年份:2013
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负责人:Bruce Furie
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依托单位:
Protein disulfide isomerases: A new class of antithrombotic targets
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批准号:8532972
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项目类别:
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资助金额:$211.36万
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财政年份:2012
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负责人:Bruce Furie
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依托单位:
Protein disulfide isomerases: A new class of antithrombotic targets
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批准号:8656766
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项目类别:
-
资助金额:$224.71万
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财政年份:2012
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负责人:Bruce Furie
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依托单位:
Protein disulfide isomerases: A new class of antithrombotic targets
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批准号:8843931
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项目类别:
-
资助金额:$223.0万
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财政年份:2012
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负责人:Bruce Furie
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依托单位:
Protein disulfide isomerases: A new class of antithrombotic targets
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批准号:8250091
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项目类别:
-
资助金额:$226.42万
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财政年份:2012
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负责人:Bruce Furie
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依托单位:
Cancer, venous thromboembolic disease and tissue factor-bearing microparticles
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批准号:8321526
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项目类别:
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资助金额:$42.08万
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财政年份:2008
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负责人:Bruce Furie
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依托单位:
Cancer, venous thromboembolic disease and tissue factor-bearing microparticles
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批准号:7690929
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项目类别:
-
资助金额:$42.5万
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财政年份:2008
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负责人:Bruce Furie
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依托单位:
Thrombus Formation In Vivo
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批准号:7347100
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项目类别:
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资助金额:$179.99万
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财政年份:2008
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负责人:Bruce Furie
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依托单位:
Cancer, venous thromboembolic disease and tissue factor-bearing microparticles
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批准号:7910620
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项目类别:
-
资助金额:$42.5万
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财政年份:2008
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负责人:Bruce Furie
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依托单位:
Thrombus Formation In Vivo
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批准号:8278624
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项目类别:
-
资助金额:$173.5万
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财政年份:2008
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负责人:Bruce Furie
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依托单位:
Thrombus Formation In Vivo
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批准号:7680997
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项目类别:
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资助金额:$174.92万
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财政年份:2008
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负责人:Bruce Furie
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依托单位:
Thrombus Formation In Vivo
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批准号:7876919
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项目类别:
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资助金额:$175.03万
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财政年份:2008
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负责人:Bruce Furie
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依托单位:
Thrombus Formation In Vivo
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批准号:8078110
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项目类别:
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资助金额:$175.22万
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财政年份:2008
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负责人:Bruce Furie
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依托单位:
Cancer, venous thromboembolic disease and tissue factor-bearing microparticles
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批准号:8114132
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项目类别:
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资助金额:$42.5万
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财政年份:2008
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负责人:Bruce Furie
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依托单位:
Factor lXa-Factor Vllla complexes in blood coagulation
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批准号:6814564
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项目类别:
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资助金额:$42.5万
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财政年份:2004
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负责人:Bruce Furie
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依托单位:
Factor lXa-Factor Vllla complexes in blood coagulation
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批准号:6921380
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项目类别:
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资助金额:$42.5万
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财政年份:2004
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负责人:Bruce Furie
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依托单位:
Factor lXa-Factor Vllla complexes in blood coagulation
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批准号:7254115
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项目类别:
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资助金额:$40.3万
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财政年份:2004
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负责人:Bruce Furie
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依托单位:
Factor lXa-Factor Vllla complexes in blood coagulation
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批准号:7093634
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项目类别:
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资助金额:$41.5万
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财政年份:2004
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负责人:Bruce Furie
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依托单位:
Factor lXa-Factor Vllla complexes in blood coagulation
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批准号:7447457
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项目类别:
-
资助金额:$40.3万
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财政年份:2004
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负责人:Bruce Furie
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依托单位:
海外基金