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.
项目摘要
哺乳动物血小板是小的无核血细胞,专门用于持续监测和保持血小板的完整性。
心血管系统(止血)。它们由骨髓中的巨核细胞(MK)产生,
它们被释放到血液中,在人体内循环10天,在小鼠体内循环5天。血小板稳态,即
建立一个明确的外周血小板计数(PPC),需要两个过程-血小板的生产和
间隙-受到严格管制。同时,血小板依赖于一种非常敏感的信号机制,
在剪切应力下促进血小板粘附和止血栓形成。这种高灵敏度,
然而,这造成了不希望的血小板活化的风险,其可导致血小板清除和/或血栓形成。
我们和其他人确定了小GTAP 1在血小板活化中的关键作用。我们进一步
证明血小板中Rap 1活性受鸟嘌呤核苷酸交换因子调节,
CalDAG-GEFI(CD-GEFI,RasGRP 2)和GTP酶激活蛋白Rasa 3(GAP 1 IP 4 BP)。CD-GEFI
感觉细胞内钙离子的微小变化,并对细胞内Rap 1的快速激活至关重要。
刺激. Rasa 3对抑制循环血小板中的CD-GEFI/Rap 1信号传导至关重要;在止血期间
然而,栓形成,其活性在血小板ADP受体接合后下调,
P2 Y12是抗血小板治疗的靶点。缺乏功能性Rasa 3的小鼠表现出严重的血小板减少症,
血小板生成受损和过早清除。根据这些和其他研究,我们得出结论,
血小板稳态和血管止血都依赖于Rap信号的严格调节,
了解这些基本过程可能对诊断和治疗
影响血小板数量和功能的疾病。利用独特的小鼠模型,原代和永生化的MK,
和临床相关的人类血小板样本,我们将研究Rap 1信号转导的关键问题,
巨核细胞和血小板:CD-GEFI和Rasa 3之间拮抗平衡的变化如何影响
血小板存活率?Rap 1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
不同的Rap 1蛋白池调节MK和血小板中的特异性细胞反应?老鼠有多相似
和人类血小板之间的关系控制Rasa 3活性的分子机制是什么
P2 Y12的下游为了检验我们发现的临床相关性,我们将研究是否增加了Rap 1信号,
由钙稳态受损诱导的血小板和MK是显著性血小板减少的根本原因。
血小板减少症中观察到的Stormorken综合征,我们将确定是否在个体间的变异性,
Rap 1信号通路导致健康个体和2型糖尿病患者对P2 Y12抑制剂耐药
糖尿病如果成功的话,这些研究可以为诊断和管理一些疾病的新策略铺平道路。
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:
8185343 - 财政年份:2011
- 资助金额:
$ 41.39万 - 项目类别:
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