Molecular and genetic basis of deep venous thrombosis
深静脉血栓形成的分子和遗传学基础
基本信息
- 批准号:10460687
- 负责人:
- 金额:$ 35.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-15 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:ARNT geneAffectAllelesAnatomyAnimalsAnticoagulantsAnticoagulationBlood PlateletsBlood VesselsBlood coagulationBlood flowCellsCessation of lifeCoagulation ProcessDataDeep Vein ThrombosisDiseaseDoppler UltrasoundEndothelial CellsEndotheliumEnvironmentF2R geneFOXC2 geneFactor IXFoundationsGene ExpressionGenesGeneticGenetic TranscriptionHealthHistologicHospitalsHumanImageImmobilizationIn VitroIncidenceInflammationInjuryInpatientsKnock-inLegLinkMeasuresMechanicsMolecularMolecular GeneticsMusMyocardial InfarctionOperative Surgical ProceduresPathogenesisPathologicPathologistPathway interactionsPhenotypePhysiologicalPhysiologyPopulationPostureProcessPulmonary EmbolismReportingResearch DesignRisk FactorsRoleSinusSiteSurgical ModelsTFPITestingThrombinThrombophiliaThrombosisThrombusTranslatingVWF geneVaricosityVeinsVenousVenous ThrombosisWorkactivated protein C receptordesignexperiencefactor V Leidengenetic approachhealthy volunteerhemodynamicshuman diseasein vivolymphatic valvemortalitymouse modelnoveloscillatory blood flowpreventprogramsprophylacticresponsetranscription factor
项目摘要
Project Summary
Deep venous thrombosis (DVT) and secondary pulmonary embolism affect 0.1-0.2% of
the population and cause 60,000-100,000 deaths annually, an incidence and mortality
similar to that of myocardial infarction. In 1856 the pathologist Rudolph Virchow
implicated changes in venous blood flow in DVT pathogenesis, but a molecular and
genetic basis for how hemodynamic changes drive DVT pathogenesis has not been
identified, and present therapy is restricted to prophylactic measures to augment venous
blood flow and systemic anticoagulation. We have recently demonstrated that the
endothelial GATA2-FOXC2-PROX1 transcriptional pathway is activated by oscillatory or
reversing flow and required to stimulate the formation of venous and lymphatic valves.
Our preliminary studies demonstrate that endothelial cells around venous valves that
experience similar oscillatory flow express the GATA2-FOXC2-PROX1 transcriptional
program in association with a strong anti-coagulant phenotype marked by low vWF, high
EPCR, high TM, and high TFPI expression. Loss of this transcriptional program
conferred by altered venous flow or genetic deletion in peri-valvular ECs results in clot
formation around the venous valve. We hypothesize that endothelial GATA2-FOXC2-
PROX1 expression stimulated by oscillatory flow maintains an anticoagulant endothelial
phenotype required to prevent DVT formation. This proposal will test this hypothesis
using a combination of genetic approaches to specifically delete the
GATA2/FOXC2/PROX1 pathway in mouse peri-valvular endothelial cells, surgical
approaches to reduce venous flow in the mouse, and histologic and physiologic studies
of human venous valves to test whether this mechanism is conserved in humans and
lost during DVT pathogenesis. These studies are expected to establish a genetic and
molecular mechanism for DVT pathogenesis that will serve as the foundation for novel
mechanical and molecular therapies.
项目摘要
深静脉血栓形成(DVT)和继发性肺血栓形成影响0.1-0.2%
每年造成60,000-100,000人死亡,发病率和死亡率
与心肌梗死相似。1856年,病理学家鲁道夫·维肖
与DVT发病机制中静脉血流的变化有关,但一个分子和
血流动力学改变如何驱动DVT发病的遗传学基础尚不清楚
已确诊,目前的治疗仅限于静脉扩张的预防性措施
血液流动和全身抗凝。我们最近已经证明了
振荡OR激活内皮细胞GATA2-FOXC2-PROX1转录途径
逆流和刺激静脉和淋巴瓣膜的形成所需。
我们的初步研究表明,静脉瓣膜周围的内皮细胞
经历类似的振荡流表达GATA2-FOXC2-PROX1转录
程序伴随着强烈的抗凝血剂表型,以低vWF,高vWF为标志
EPCR、高TM、高TFPI表达。丢失这个转录程序
瓣膜周围内皮细胞内静脉血流改变或基因缺失导致血栓
在静脉瓣膜周围形成。我们假设内皮细胞GATA2-FOXC2-
振荡流刺激的PROX1表达维持抗凝内皮细胞
防止DVT形成所需的表型。这项提议将检验这一假设。
使用遗传方法的组合来特别删除
外科手术小鼠瓣膜周围内皮细胞GATA2/FOXC2/PROX1通路
减少小鼠静脉血流量的方法以及组织学和生理学研究
以测试这一机制是否在人类和
在深静脉血栓形成过程中丢失。这些研究有望建立一种遗传和
DVT发病的分子机制将成为新的
机械和分子疗法。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Defects in vein valve PROX1/FOXC2 antithrombotic pathway in endothelial cells drive the hypercoagulable state induced by trauma and critical illness.
内皮细胞中静脉瓣膜 PROX1/FOXC2 抗血栓通路的缺陷导致创伤和危重疾病引起的高凝状态。
- DOI:10.1097/ta.0000000000003945
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Hoofnagle,MarkH;Hess,Annie;Nalugo,Margaret;Ghosh,Sarbani;Hughes,Shin-Wen;Fuchs,Anja;Welsh,JohnD;Kahn,MarkL;Bochicchio,GrantV;Randolph,GwendalynJ;Leonard,JenniferM;Turnbull,IsaiahR
- 通讯作者:Turnbull,IsaiahR
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{{ truncateString('MARK L KAHN', 18)}}的其他基金
Genetic Investigation of Covid 19 in Lung Disease
Covid 19 在肺部疾病中的基因研究
- 批准号:
10673004 - 财政年份:2022
- 资助金额:
$ 35.88万 - 项目类别:
Reciprocal VEGFC/VEGFR3-CDH5 regulation of lymphatic and sinusoidal vascular growth
VEGFC/VEGFR3-CDH5 对淋巴管和窦状血管生长的相互调节
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10417684 - 财政年份:2022
- 资助金额:
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Covid 19 在肺部疾病中的基因研究
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10502908 - 财政年份:2022
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Covid 19 在肺部疾病中的基因研究
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10768221 - 财政年份:2022
- 资助金额:
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VEGFC/VEGFR3-CDH5 对淋巴管和窦状血管生长的相互调节
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10608143 - 财政年份:2022
- 资助金额:
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Flow and endothelial signaling in acquired myxomatous valve disease
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10226236 - 财政年份:2020
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Flow and endothelial signaling in acquired myxomatous valve disease
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10626893 - 财政年份:2020
- 资助金额:
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Flow and endothelial signaling in acquired myxomatous valve disease
获得性粘液瘤性瓣膜疾病中的血流和内皮信号传导
- 批准号:
10033435 - 财政年份:2020
- 资助金额:
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Flow and endothelial signaling in acquired myxomatous valve disease
获得性粘液瘤性瓣膜疾病中的血流和内皮信号传导
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10408810 - 财政年份:2020
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MEKK3 signaling in hemogenic endothelium
造血内皮细胞中的 MEKK3 信号传导
- 批准号:
10198023 - 财政年份:2018
- 资助金额:
$ 35.88万 - 项目类别:
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