The Role of Tissue Factor: FVIIa-PAR-2 Signaling in Heart Ischemia/Reperfusion
组织因子的作用:FVIIa-PAR-2 信号在心脏缺血/再灌注中的作用
基本信息
- 批准号:8428592
- 负责人:
- 金额:$ 34.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-12-15 至 2015-11-30
- 项目状态:已结题
- 来源:
- 关键词:AttenuatedBlood Coagulation FactorCardiacCardiac MyocytesCellsCicatrixClinicalCoagulation ProcessCollagenComplexDataDevelopmentExtravasationFactor VIIaFibrin split productsFibrosisFunctional disorderGenerationsGoalsGrowthHeartHeart failureInfarctionInflammationInflammatoryLeadModelingMorbidity - disease rateMyocardial InfarctionMyocardial IschemiaMyocardial tissueMyocardiumOutcomeOxidative StressPAR-1 ReceptorPAR-2 ReceptorPathologicPathway interactionsPlayProductionPropertyReactive Oxygen SpeciesReperfusion InjuryReperfusion TherapyRoleSignal TransductionThrombinThromboplastinTimeTissuesWestern Worldchemokinecytokineheart functionimprovedin vivoinjuredmortalitymouse modelmyocardial infarct sizingneutrophilnovel strategiespreventtool
项目摘要
Myocardial infarction induced by ischemia/reperfusion (I/R) injury is a major clinical
problem. During I/R injury, damage to the endothelial barrier allows a leakage of
coagulation factors into the myocardium. Tissue factor (TF), the primary activator of the
coagulation cascade, is constitutively expressed in the heart. Activation of coagulation
cascade by TF has been shown to play a role in myocardial infarction after I/R injury.
However, the role TF:FVIIa signaling has not been investigated.
The TF:FVIIa complex can activate cells by cleavage of protease activated receptor-2
(PAR-2). Both TF and PAR-2 are expressed on cardiomyocytes as well as neutrophils,
which infiltrate into the myocardium after I/R injury. My preliminary data demonstrate
that PAR-2 deficiency results in significant reduction of infarct size, heart remodeling
and heart dysfunction after I/R injury. In this proposal I hypothesize that TF:FVIIa-
dependent activation of PAR-2 on both neutrophils and cardiomyocytes contributes to
myocardial infarction and heart remodeling. The proposal has two specific aims. In
Specific Aim 1 I will investigate the role of TF:FVIIa-dependent activation of PAR-2 in
infarct size using an in vivo mouse model of short-term I/R injury. In Specific Aim 2 I
will determine how TF:FVIIa-PAR-2 pathway contributes to heart remodeling after long-
term I/R injury.
In my proposal I will use unique set of tools that allow me to distinguish between
signaling and coagulation properties of TF:FVIIa complex. Understanding the role of
TF:FVIIa-dependent activation of PAR-2 in injured heart may lead to the development of
new therapies to reduce myocardial infarction and heart failure.
缺血/再灌注(I/R)损伤导致的心肌梗死是临床上的一个主要问题,
问题.在I/R损伤过程中,内皮屏障的损伤允许血管内皮细胞的渗漏。
凝血因子进入心肌。组织因子(TF),主要的激活剂,
凝血级联,在心脏中组成型表达。激活凝血
TF的级联反应在I/R损伤后的心肌梗死中起作用。
然而,TF:FVIIa信号传导的作用尚未被研究。
TF:FVIIa复合物可通过切割蛋白酶激活的受体-2来激活细胞
(PAR-2)。TF和PAR-2都在心肌细胞以及中性粒细胞上表达,
I/R损伤后,其浸润到心肌中。我的初步数据显示
PAR-2缺乏导致梗死面积显著减小,心脏重塑
I/R损伤后的心脏功能障碍。在这个建议中,我假设TF:FVIIa-
PAR-2在中性粒细胞和心肌细胞上的依赖性激活有助于
心肌梗死和心脏重塑。该提案有两个具体目标。在
具体目的1我将研究TF:FVIIa依赖性PAR-2激活在
使用短期I/R损伤的体内小鼠模型测量梗死面积。特别目标2
将确定TF:FVIIa-PAR-2通路如何促进长期心脏重塑,
长期I/R损伤
在我的建议中,我将使用一套独特的工具,使我能够区分
TF:FVIIa复合物的信号传导和凝血性质。理解的作用
TF:损伤心脏中PAR-2的FVIIa依赖性激活可能导致
减少心肌梗死和心力衰竭的新疗法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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RAFAL L PAWLINSKI其他文献
RAFAL L PAWLINSKI的其他文献
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{{ truncateString('RAFAL L PAWLINSKI', 18)}}的其他基金
Mechanisms of coagulation-dependent pathologies in sickle cell disease
镰状细胞病凝血依赖性病理机制
- 批准号:
9762664 - 财政年份:2018
- 资助金额:
$ 34.49万 - 项目类别:
Mechanisms of coagulation-dependent pathologies in sickle cell disease
镰状细胞病凝血依赖性病理机制
- 批准号:
10178080 - 财政年份:2018
- 资助金额:
$ 34.49万 - 项目类别:
The Role of Tissue Factor: FVIIa-PAR-2 Signaling in Heart Ischemia/Reperfusion
组织因子的作用:FVIIa-PAR-2 信号传导在心脏缺血/再灌注中的作用
- 批准号:
8599478 - 财政年份:2010
- 资助金额:
$ 34.49万 - 项目类别:
The Role of Tissue Factor: FVIIa-PAR-2 Signaling in Heart Ischemia/Reperfusion
组织因子的作用:FVIIa-PAR-2 信号传导在心脏缺血/再灌注中的作用
- 批准号:
8039581 - 财政年份:2010
- 资助金额:
$ 34.49万 - 项目类别:
The Role of Tissue Factor: FVIIa-PAR-2 Signaling in Heart Ischemia/Reperfusion
组织因子的作用:FVIIa-PAR-2 信号在心脏缺血/再灌注中的作用
- 批准号:
8803678 - 财政年份:2010
- 资助金额:
$ 34.49万 - 项目类别:
The Role of Tissue Factor: FVIIa-PAR-2 Signaling in Heart Ischemia/Reperfusion
组织因子的作用:FVIIa-PAR-2 信号传导在心脏缺血/再灌注中的作用
- 批准号:
8207215 - 财政年份:2010
- 资助金额:
$ 34.49万 - 项目类别:
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