PAR4 mediates platelet activation in venous thromboembolism
PAR4介导静脉血栓栓塞中的血小板活化
基本信息
- 批准号:10387302
- 负责人:
- 金额:$ 4.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAgonistAllelesAnticoagulantsAntiplatelet DrugsBinding SitesBiological MarkersBloodBlood PlateletsBlood flowCancer PatientCardiovascular DiseasesCessation of lifeClinicalClinical TrialsCoagulation ProcessComplicationDataDevelopmentDiseaseEndothelial CellsErythrocytesExhibitsFibrinFunctional disorderG-Protein-Coupled ReceptorsGTP-Binding Protein alpha Subunits, GsGenerationsGenetic PolymorphismGoalsHemorrhageHumanIndividualInflammatoryKnock-in MouseLigand BindingMediatingMeta-AnalysisMicrofluidicsModelingMusMutationNew AgentsOnset of illnessPAWR genePathway interactionsPatientsPeptidesPharmacologyPlatelet ActivationPlayPreventionPreventive measureProcessPublicationsPulmonary EmbolismRecurrenceRelative RisksResearchResearch PersonnelRiskRisk FactorsRisk ReductionRoleSafetySerineSeveritiesSignal TransductionSingle Nucleotide PolymorphismSurfaceTestingTherapeuticThrombinThrombophiliaThrombosisThrombusTriad Acrylic ResinVariantVenous ThrombosisWorkbasechemotherapyclinical applicationextracellulargenome wide association studyimprovedin vivoinsightknock-downmouse modelmouse protease-activated receptor 4neutrophilnew therapeutic targetplatelet functionpreventpromoterprotease-activated receptor 3protease-activated receptor 4receptorresponsesmall molecule inhibitorthrombotictraining opportunityvenous thromboembolism
项目摘要
PROJECT SUMMARY/ABSTRACT
Venous thrombosis (VT) and its major complication, pulmonary embolism (PE), are often grouped together as
venous thromboembolism (VTE). This disease affects nearly 600,000 individuals per year and is the leading
cause of end-stage cardiovascular disease and death. VT is promoted by three major factors, known as
Virchow’s triad: hypercoagulability, endothelial cell dysfunction, and stasis of blood flow. It is now recognized
that platelets play a critical initiating role, and the mechanism is just now being uncovered. Hypercoagulation
and thrombin generation are major risk factors for VT, and thrombin-activated protease activated receptor 4
(PAR4) promotes procoagulant platelets, phosphatidyl serine (PS) exposure, and subsequent thrombin
generation. I propose that platelet PAR4 is an important contributor to VTE. The scientific premise of this proposal
is based my preliminary data showing that a hypo-reactive PAR4 single nucleotide polymorphism (SNP) (PAR4-
P310L) located in extracellular loop 3 of PAR4 is associated with a lower risk for VTE in a GWAS meta-analysis.
Further, mouse platelets with a homologous PAR4-P322L polymorphism exhibit decreased aggregation in
response to thrombin activation and ultimately show decreased PAR4 receptor reactivity. The goals of this
proposal are 1) to determine how PAR4 contributes to VT initiation and propagation using complementary mouse
models, 2) validate PAR4 as a target to treat VT 3) define how PAR4 modulates platelet function in VT. I
hypothesize that PAR4 signaling on platelets is a driver of VT, and reduced PAR4 signaling or pharmacological
inhibition will offer protection from VTE. I aim to determine the role of PAR4 in the initiation and propagation of
venous thrombosis. I will use 3 complementary mouse models of VT to establish PAR4 as a major contributor of
clot development under different thrombotic conditions. In order to determine the level of PAR4 reactivity
necessary for thrombus propagation, I will use 3 mouse models with differing levels of PAR4 activity: wild-type,
PAR4-P322L mimicking the human SNP, and PAR4 -/- to completely remove PAR4. Additionally, this proposal
aims to define how PAR4 activation modulates platelet response in VTE. I will use human blood in microfluidic
chambers as well as mouse models with varying levels of PAR4 reactivity described above to determine how
PAR4 influences the development of VT. Upon completion, this proposal will identify an undetermined
mechanism behind PAR4-mediated platelet procoagulant activity in VTE, which can provide a novel therapeutic
target for patients with VTE.
项目概要/摘要
静脉血栓(VT)及其主要并发症肺栓塞(PE)通常被归为一类:
静脉血栓栓塞 (VTE) 每年影响近 600,000 人,是主要疾病。
导致终末期心血管疾病和死亡的原因有以下三个主要因素:
魏尔啸三联征:高凝状态、内皮细胞功能障碍和血流停滞现已得到认可。
血小板起着关键的启动作用,其机制刚刚被揭示。
和凝血酶生成是 VT 的主要危险因素,凝血酶激活的蛋白酶激活受体 4
(PAR4) 促进促凝血血小板、磷脂酰丝氨酸 (PS) 暴露以及随后的凝血酶
我认为血小板 PAR4 是 VTE 的重要贡献者。
基于我的初步数据,显示低反应性 PAR4 单核苷酸多态性 (SNP) (PAR4-
GWAS 荟萃分析显示,位于 PAR4 细胞外环 3 的 P310L)与较低的 VTE 风险相关。
此外,具有同源 PAR4-P322L 多态性的小鼠血小板在
对凝血酶激活的反应并最终显示 PAR4 受体反应性降低。
建议是 1) 使用互补小鼠确定 PAR4 如何促进 VT 启动和传播
模型,2) 验证 PAR4 作为治疗 VT 的靶点 3) 定义 PAR4 如何调节 VT 中的血小板功能。
血小板上的 PAR4 信号传导是 VT 的驱动因素,并且减少 PAR4 信号传导或药理作用
抑制将提供对 VTE 的保护 我的目的是确定 PAR4 在 VTE 的启动和传播中的作用。
我将使用 3 个互补的 VT 小鼠模型来确定 PAR4 作为 VT 的主要贡献者。
不同血栓条件下的血栓形成以确定 PAR4 反应性水平。
对于血栓传播所必需的,我将使用 3 种具有不同 PAR4 活性水平的小鼠模型:野生型、
PAR4-P322L 模仿人类 SNP,以及 PAR4 -/- 以完全去除 PAR4。
旨在确定 PAR4 激活如何调节 VTE 中的血小板反应 我将在微流体中使用人血。
室以及具有上述不同水平 PAR4 反应性的小鼠模型,以确定如何
PAR4影响VT的发展。完成后,该提案将确定一个未确定的问题。
PAR4介导的VTE血小板促凝活性背后的机制,可以提供一种新的治疗方法
VTE 患者的目标。
项目成果
期刊论文数量(0)
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Elizabeth Ann Knauss其他文献
Elizabeth Ann Knauss的其他文献
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{{ truncateString('Elizabeth Ann Knauss', 18)}}的其他基金
PAR4 mediates platelet activation in venous thromboembolism
PAR4介导静脉血栓栓塞中的血小板活化
- 批准号:
10794920 - 财政年份:2022
- 资助金额:
$ 4.56万 - 项目类别:
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