Rap1 signaling in platelet homeostasis and vascular hemostasis
Rap1 信号在血小板稳态和血管止血中的作用
基本信息
- 批准号:9330204
- 负责人:
- 金额:$ 41.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-15 至 2020-05-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseADP ReceptorsAddressAdhesionsAdhesivesAffectAgonistAlpha GranuleBloodBlood CellsBlood CirculationBlood PlateletsBlood VesselsBone MarrowCalciumCardiovascular systemCell AdhesionCell membraneCell physiologyCellsClinicalCollagenComplement Factor BCoupledCytoplasmic GranulesDevelopmentDiagnosisDiglyceridesDiseaseEquilibriumEventExhibitsFibrinogenG-substrateGTP-Binding ProteinsGTPase-Activating ProteinsGenerationsGuanine Nucleotide Exchange FactorsGuanosine TriphosphateGuanosine Triphosphate PhosphohydrolasesHalf-LifeHemostatic AgentsHemostatic functionHeterogeneityHomeostasisHumanHuman PathologyITAMImpairmentIn VitroIndividualInheritedInjuryInositolIntegrinsLeadLinkMediatingMegakaryocytesModelingMolecularMonitorMonomeric GTP-Binding ProteinsMusNon-Insulin-Dependent Diabetes MellitusNucleotidesPathologyPathway interactionsPeripheralPhospholipase CPlatelet ActivationPlatelet Count measurementProcessProductionProtein IsoformsProtein Kinase CProteinsRegulationResearchResistanceRiskRoleSamplingSignal PathwaySignal TransductionSiteSyndromeTestingThrombinThrombocytopeniaThrombosisThromboxane A2ThrombusTimeTranslatingWorkbasechemical geneticsclinically relevantclopidogrelgenetic approachin vivoindividual patientinhibitor/antagonistmouse modelnovel strategiespersonalized approachpodoplaninprematurepreventreceptorresponseshear stress
项目摘要
PROJECT SUMMARY
Mammalian platelets are small anucleate blood cells specialized to continuously monitor and preserve the integrity of
the cardiovascular system (hemostasis). They are produced by megakaryocytes (MKs) in the bone marrow and
released into blood, where they circulate for ten days in humans and five days in mice. Platelet homeostasis, i.e. the
establishment of a defined peripheral platelet count (PPC), requires that both processes - platelet production and
clearance - are tightly regulated. At the same time, platelets depend on a very sensitive signaling machinery that
facilitates platelet adhesion and hemostatic plug formation under shear stress. This high sensitivity,
however, poses a risk for unwanted platelet activation that can lead to platelet clearance and/or thrombosis.
We and others identified a critical role for the small GTPase Rap1 in platelet activation. We further
demonstrated that Rap1 activity in platelets is regulated by the guanine nucleotide exchange factor,
CalDAG-GEFI (CD-GEFI, RasGRP2), and the GTPase-activating protein, Rasa3 (GAP1IP4BP). CD-GEFI
senses small changes in intracellular calcium and is crucial for the rapid activation of Rap1 upon cellular
stimulation. Rasa3 is critical to restrain CD-GEFI/Rap1 signaling in circulating platelets; during hemostatic
plug formation, however, its activity is downregulated after engagement of the platelet ADP receptor,
P2Y12, the target of antiplatelet therapy. Mice lacking functional Rasa3 exhibit severe thrombocytopenia, caused
by impaired production and premature clearance of platelets. Based on these and other studies we concluded
that both platelet homeostasis and vascular hemostasis depend on a tight regulation of Rap signaling, and that a better
understanding of these fundamental processes may have important implications in the diagnosis and treatment of
disorders that affect platelet number and function. Utilizing unique mouse models, primary and immortilized MKs,
and clinically relevant human platelet samples, we will study key questions concerning Rap1 signaling in
megakaryocytes and platelets: how does a shift in the antagonistic balance between CD-GEFI and Rasa3 affect
platelet survival? What is the role of Rap1 signaling in megakaryocyte development and platelet production? Are their
different pools of Rap1 protein that regulate specific cellular responses in MKs and platelets? How similar are mouse
and human platelets with regard to Rap1 signaling? What are the molecular mechanisms controlling Rasa3 activity
downstream of P2Y12? To test the clinical relevance of our findings, we will investigate if increased Rap1 signaling in
platelets and MKs, induced by impaired calcium homeostasis, is the underlying cause of the marked
thrombocytopenia observed in Stormorken syndrome, and we will determine whether interindividual variability in the
Rap1 signaling pathway contributes to P2Y12 inhibitor resistance in healthy individuals and patients with type 2
diabetes. If successful, these studies could pave the way to novel strategies for diagnosing and managing some of
the inherited and acquired thrombocytopenias, and to a more personalized approach to anti-platelet therapy.
项目总结
哺乳动物的血小板是一种小的无核血细胞,专门用于持续监测和维持
心血管系统(止血)。它们由骨髓中的巨核细胞(MK)产生,
释放到血液中,在人类体内循环10天,在老鼠体内循环5天。血小板动态平衡,即
建立明确的外周血小板计数(PPC),需要两个过程-血小板产生和
通关--受到严格监管。同时,血小板依赖于一种非常敏感的信号机制
在剪切力作用下,促进血小板黏附和止血栓的形成。这种高度的敏感性,
然而,这会带来不必要的血小板激活的风险,这可能导致血小板清除和/或血栓形成。
我们和其他人确定了小GTP酶Rap1在血小板激活中的关键作用。我们进一步
证明了血小板中的Rap1活性受鸟嘌呤核苷酸交换因子的调节,
CalDAG-GEFI(CD-GEFI,RasGRP2)和GTP酶激活蛋白Rasa3(GAP1IP4BP)。CD-GEFI
感知细胞内钙的微小变化,并对RAP1在细胞内的快速激活至关重要
刺激。在止血过程中,Rasa3对抑制循环中的血小板CD-GEFI/Rap1信号至关重要
然而,塞子的形成在与血小板ADP受体结合后其活性被下调,
P2Y12是抗血小板治疗的靶点。缺乏功能性Rasa3的小鼠表现出严重的血小板减少症,引起
由于生产受损和过早清除血小板所致。基于这些和其他研究,我们得出结论
血小板动态平衡和血管止血都依赖于对Rap信号的严格调控,而且这是一种更好的
对这些基本过程的了解可能对临床诊断和治疗具有重要意义。
影响血小板数量和功能的疾病。利用独特的小鼠模型,原始的和永生的MK,
和临床相关的人类血小板样本,我们将研究与Rap1信号转导有关的关键问题
巨核细胞和血小板:CD-GEFI和Rasa3之间拮抗平衡的改变如何影响
血小板存活?RAP1信号在巨核细胞发育和血小板生成中的作用是什么?是他们的
调节巨噬细胞和血小板中特定细胞反应的不同的Rap1蛋白池?鼠标有多相似?
和人类血小板有关的Rap1信号吗?控制Rasa3活性的分子机制是什么?
在2012年的下游?为了测试我们的发现的临床相关性,我们将调查RAP1信号在
由钙稳态受损引起的血小板和巨噬细胞集落刺激因子是显著的
在Stormorken综合征中观察到了血小板减少,我们将确定在
RAP1信号通路参与了健康个体和2型患者对P2Y12抑制剂的抵抗
糖尿病。如果成功,这些研究可能为诊断和管理一些新的战略铺平道路
遗传性和获得性血小板减少症,以及更个性化的抗血小板治疗方法。
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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Wolfgang Bergmeier其他文献
Wolfgang Bergmeier的其他文献
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{{ truncateString('Wolfgang Bergmeier', 18)}}的其他基金
The Hemostasis, Thrombosis, and Inflammation Models Core
止血、血栓形成和炎症模型核心
- 批准号:
10676889 - 财政年份:2020
- 资助金额:
$ 41.39万 - 项目类别:
The Hemostasis, Thrombosis, and Inflammation Models Core
止血、血栓形成和炎症模型核心
- 批准号:
10229367 - 财政年份:2020
- 资助金额:
$ 41.39万 - 项目类别:
Small GTPases in the biology of platelets and megakaryocytes
血小板和巨核细胞生物学中的小 GTP 酶
- 批准号:
9899304 - 财政年份:2019
- 资助金额:
$ 41.39万 - 项目类别:
Small GTPases in the biology of platelets and megakaryocytes
血小板和巨核细胞生物学中的小 GTP 酶
- 批准号:
10577770 - 财政年份:2019
- 资助金额:
$ 41.39万 - 项目类别:
Small GTPases in the biology of platelets and megakaryocytes
血小板和巨核细胞生物学中的小 GTP 酶
- 批准号:
10377385 - 财政年份:2019
- 资助金额:
$ 41.39万 - 项目类别:
2017 The Cell Biology of Megakaryocytes & Platelets Gordon Research Conference & Gordon Research Seminar
2017 巨核细胞的细胞生物学
- 批准号:
9248106 - 财政年份:2017
- 资助金额:
$ 41.39万 - 项目类别:
Spatial regulation of platelet activation by Podoplanin-Clec2 signaling
Podoplanin-Clec2 信号传导对血小板活化的空间调节
- 批准号:
8761615 - 财政年份:2014
- 资助金额:
$ 41.39万 - 项目类别:
Novel strategies to prevent FcgRIIA-dependent platelet activation and thrombosis
预防 FcgRIIA 依赖性血小板活化和血栓形成的新策略
- 批准号:
8501660 - 财政年份:2011
- 资助金额:
$ 41.39万 - 项目类别:
Novel strategies to prevent FcgRIIA-dependent platelet activation and thrombosis
预防 FcgRIIA 依赖性血小板活化和血栓形成的新策略
- 批准号:
8321894 - 财政年份:2011
- 资助金额:
$ 41.39万 - 项目类别:
Novel strategies to prevent FcgRIIA-dependent platelet activation and thrombosis
预防 FcgRIIA 依赖性血小板活化和血栓形成的新策略
- 批准号:
8693003 - 财政年份:2011
- 资助金额:
$ 41.39万 - 项目类别:
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- 批准号:
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