Tissue factor-dependent coagulation in thrombosis and immune responses
血栓形成和免疫反应中的组织因子依赖性凝血
基本信息
- 批准号:10558720
- 负责人:
- 金额:$ 93.3万
- 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:2021-02-01 至 2028-01-31
- 项目状态:未结题
- 来源:
- 关键词:AffinityAtherosclerosisBacterial InfectionsBiological AssayBiological MarkersCancer PatientChoristomaClinicalCoagulation ProcessComplexCoxsackie VirusesDisseminated Intravascular CoagulationEndotoxemiaF2R geneFundingFunding MechanismsGenerationsGoalsGrantGrowthHealthHeartHemostatic functionHumanImmune responseInfectionInfluenza A Virus, H1N1 SubtypeInfluenza A virusInnate Immune ResponseIntegral Membrane ProteinKnowledgeLungMalignant NeoplasmsMalignant neoplasm of pancreasMeasuresModelingMusMyocarditisNational Heart, Lung, and Blood InstitutePathologicPathway interactionsPeptide HydrolasesPlasmaPlayProteinase-Activated ReceptorsProteomicsReperfusion InjuryRiskRisk MarkerRoleSamplingSignal TransductionSourceSystemThrombinThromboplastinThrombosisTimeTumor-DerivedVenous ThrombosisViralVirus Diseasesenhancing factorextracellular vesicleshigh rewardhigh riskhuman modelimprovedinfluenza A pneumoniamouse modelnew technologynovelnovel therapeuticspancreatic cancer patientspancreatic neoplasmpathogenpreventprotein functionreceptorresponsethrombotictumortumor growthvenous thromboembolism
项目摘要
Tissue factor (TF) is a transmembrane protein that functions as a high-affinity receptor for factor (F)VII and
FVIIa. The TF-FVIIa complex is the primary initiator of coagulation and plays an essential role in hemostasis.
However, aberrant TF expression underlies most forms of thrombosis. TF expression is also induced in response
to bacterial and viral infections as part of the innate immune response. This expression can be either protective
by limiting the spread of the pathogen or pathologic by triggering disseminated intravascular coagulation (DIC).
TF-dependent generation of coagulation proteases also leads to activation of protease-activated receptors
(PARs). My lab has made major contributions to understanding the roles of TF, coagulation proteases and PARs
in hemostasis, thrombosis, endotoxemia, ischemia-reperfusion injury, atherosclerosis, and viral infections. This
R35 OIA application is an extension of two NHLBI funded R01 grants: Mechanism of venous thrombosis in
pancreatic cancer; Role of the thrombin PAR1 pathway in viral infection. We have shown that levels of circulating
tumor-derived, TF+ extracellular vesicles (EVs) are associated with increased venous thromboembolism in
pancreatic cancer patients. In addition, we found that TF+ EVs enhance venous thrombosis in mice bearing
human pancreatic tumors. We have also shown that TF-dependent activation of coagulation and PAR1 signaling
is protective in response to Coxsackievirus B3 by boosting the antiviral IFNβ pathway in the heart. In contrast,
PAR1 suppresses the pathologic NF-κB response in the lung in response to influenza A H1N1 infection. The OIA
funding mechanism would provide stable funding and increased time for our group to pursue higher risk-higher
reward projects, such as performing proteomic analysis of plasma and EVs, establish new technologies, such
as the ExoView system, and following up on exciting discoveries. Our long-term goals are to further
understand the protective and pathologic roles of TF, coagulation proteases and PARs in cancer and
infections. There are two hypotheses for this proposal: 1/ TF enhances venous thrombosis and tumor growth
in pancreatic cancer, and 2/ TF-dependent activation of coagulation is both protective and pathologic in response
to viral infection. We will continue our studies on the identification of plasma biomarkers of thrombotic risk in
cancer patients using clinical samples. We will identify prothrombotic pathways that contribute to cancer-
associated thrombosis using mouse models. In addition, we will determine the roles of tumor and host derived
TF in the growth of pancreatic tumors in mice. We will identify the cellular sources of pathologic TF in mouse
models of viral infection that may lead to new treatments to prevent DIC. We will elucidate how PAR1 is protective
by both enhancing the IFNβ antiviral pathway in the heart and suppressing the pathologic NF-κB pathway in the
lung in response to viral infection. This knowledge may lead to the identification of new biomarkers of thrombotic
risk, treatments for pancreatic cancer and protection from viral infection.
组织因子(Tf)是一种跨膜蛋白,其功能是作为因子(F)VII的高亲和力受体
FVIIA。Tf-FVIIa复合体是凝血的主要引发物,在止血中起着至关重要的作用。
然而,TF的异常表达是大多数形式血栓形成的基础。作为回应,Tf的表达也被诱导
细菌和病毒感染是先天免疫反应的一部分。这种表达既可以是保护性的
通过触发弥散性血管内凝血(DIC)来限制病原体或病原体的传播。
依赖于Tf的凝血酶的产生也导致了蛋白水解酶激活的受体的激活
(Pars)。我的实验室在理解转铁蛋白、凝血酶和PARs的作用方面做出了重大贡献。
用于止血、血栓形成、内毒素血症、缺血再灌注损伤、动脉粥样硬化和病毒感染。这
R35 OIA应用是NHLBI资助的两个R01赠款的扩展:静脉血栓形成的机制
胰腺癌;凝血酶PAR1途径在病毒感染中的作用。我们已经证明了循环的水平
肿瘤来源的Tf+细胞外小泡(EV)与静脉血栓栓塞症的增加有关
胰腺癌患者。此外,我们还发现,Tf+EVS增强了小鼠的静脉血栓形成。
人类胰腺肿瘤。我们还证明了依赖于Tf的凝血和PAR1信号的激活
通过促进心脏中抗病毒干扰素β途径来保护对柯萨奇病毒B3的反应。相比之下,
PAR1抑制肺内对甲型H1N1流感感染的病理性核因子-κB反应。内审办
融资机制将为我们的集团提供稳定的资金和更多的时间来追求更高的风险-更高
奖励项目,如对血浆和电动汽车进行蛋白质组分析,建立新技术,如
作为ExoView系统,并跟进令人兴奋的发现。我们的长期目标是进一步
了解转铁蛋白、凝血酶和PARs在癌症和癌症中的保护作用和病理作用
感染。这一提议有两个假设:1/Tf促进静脉血栓形成和肿瘤生长
在胰腺癌中,依赖于2/TF的凝血激活既是保护性的,也是病理反应
病毒感染。我们将继续研究血栓形成风险的血浆生物标志物的识别。
癌症患者使用临床样本。我们将确定导致癌症的血栓前途径-
使用小鼠模型进行相关血栓形成。此外,我们还将确定肿瘤和宿主来源的作用
转铁蛋白在小鼠胰腺肿瘤生长中的作用。我们将确定小鼠病理性转铁蛋白的细胞来源
可能导致预防DIC的新疗法的病毒感染模型。我们将阐明PAR1是如何保护
通过增强心脏中干扰素β抗病毒途径和抑制病理性核因子-κB途径
肺部对病毒感染的反应。这一知识可能有助于识别血栓形成的新生物标志物。
风险、胰腺癌的治疗和预防病毒感染。
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)
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Nigel Mackman其他文献
Nigel Mackman的其他文献
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{{ truncateString('Nigel Mackman', 18)}}的其他基金
Role of the Thrombin PAR-1 Pathway in Viral Infection
凝血酶 PAR-1 途径在病毒感染中的作用
- 批准号:
9380482 - 财政年份:2013
- 资助金额:
$ 93.3万 - 项目类别:
Role of the Thrombin PAR-1 Pathway in Viral Infection
凝血酶 PAR-1 途径在病毒感染中的作用
- 批准号:
8558940 - 财政年份:2013
- 资助金额:
$ 93.3万 - 项目类别:
Role of the Thrombin PAR-1 Pathway in Viral Infection
凝血酶 PAR-1 途径在病毒感染中的作用
- 批准号:
8891487 - 财政年份:2013
- 资助金额:
$ 93.3万 - 项目类别:
Role of the Thrombin PAR-1 Pathway in Viral Infection
凝血酶 PAR-1 途径在病毒感染中的作用
- 批准号:
8706957 - 财政年份:2013
- 资助金额:
$ 93.3万 - 项目类别:
2010 Hemostasis Gordon Research Conference and/or Gordon Research Seminar
2010 止血戈登研究会议和/或戈登研究研讨会
- 批准号:
7911112 - 财政年份:2010
- 资助金额:
$ 93.3万 - 项目类别:
Role of PAR-1 and PAR-2 in Cardiac Remodeling
PAR-1 和 PAR-2 在心脏重构中的作用
- 批准号:
7891220 - 财政年份:2007
- 资助金额:
$ 93.3万 - 项目类别:
Role of PAR-1 and PAR-2 in Cardiac Remodeling
PAR-1 和 PAR-2 在心脏重构中的作用
- 批准号:
7487314 - 财政年份:2007
- 资助金额:
$ 93.3万 - 项目类别:
Role of PAR-1 and PAR-2 in Cardiac Remodeling
PAR-1 和 PAR-2 在心脏重构中的作用
- 批准号:
7666964 - 财政年份:2007
- 资助金额:
$ 93.3万 - 项目类别:
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