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
基本信息
- 批准号:10577770
- 负责人:
- 金额:$ 84.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-03-21 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AdhesionsBiochemicalBiologicalBiological AssayBiologyBiosensorBloodBlood CellsBlood Coagulation DisordersBlood PlateletsBlood VesselsBone MarrowCardiovascular systemCellsClinical ResearchDeep Vein ThrombosisDevelopmentDiagnosisDiseaseFundingFutureGoalsGrantGuanosine Triphosphate PhosphohydrolasesHemorrhageHemostatic AgentsHemostatic functionHumanIn VitroInflammationInheritedLifeMegakaryocytesMolecularMolecular ProfilingMonitorMonomeric GTP-Binding ProteinsMusMyocardial InfarctionNational Heart, Lung, and Blood InstitutePathologyPathway interactionsPeripheralPhagocytesPlatelet ActivationPlatelet Count measurementPrevention approachProcessProductionProliferatingRegulationRiskRoleSignal TransductionThrombocytopeniaThrombosisVenous ThrombosisWorkimprovedinhibitorinter-individual variationmouse modelnovelnovel strategiesoptogeneticspersonalized approachplatelet functionplatelet homeostasispodoplaninpreservationrhoshear stressthrombotic complicationstooltransfusion medicine
项目摘要
ABSTRACT
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 until they
get cleared by phagocytes. Platelet homeostasis, i.e. the establishment of a defined peripheral platelet count,
requires tight regulation of both platelet production and clearance. To fulfill their hemostatic function, platelets
depend on a very sensitive signaling machinery that facilitates platelet adhesion under shear stress. This high
sensitivity, however, poses a risk for unwanted platelet activation that can lead to platelet clearance and/or
thrombosis. The overarching goal of our work is to achieve a better understanding of the molecular
mechanisms regulating MK development and platelet reactivity, with a specific focus on the role of small
GTPases in these processes. This R35 OIA application is an extension to three funded NHLBI R01 grants:
Small GTPases in Megakaryocyte Biology; Rap1 Signaling in Platelet Homeostasis and Vascular Hemostasis;
Spatial Regulation of Platelet Activation by Podoplanin-Clec2 Signaling. Our MK studies utilize unique
biosensors to establish a molecular signature of small GTPase activity (both Rho and Rap GTPases) during
the final stages of development, including the transition from proliferation to proplatelet formation. Once
established, we will establish proof-of-principle that precisely targeted perturbation of GTPase activity by
optogenetic tools is a viable strategy to optimize in vitro platelet production, a hot topic in Transfusion
Medicine. Our platelet work focuses more specifically on the role of Rap GTPases as master regulators of
cellular activation and hemostatic plug formation. We have utilized unique mouse models to establish the
importance and the key regulators of Rap1 signaling during platelet activation. Furthermore, we have shown
that Rap1 activity has to be tightly balanced both in quiescent, circulating and in hemostatically active platelets,
and that disturbance of this pathway leads to bleeding or thrombocytopenia/ thrombosis. In ongoing and future
work, we will expand on our cell biological and biochemical/-physical studies to provide a comprehensive
understanding of how Rap signaling controls platelet function, how it is regulated, and if/ how it contributes to
other patho-physiological processes such as vascular integrity in development/ inflammation and venous
thrombosis. We will use our unique biochemical assays to screen for inhibitors of Rap signaling. Our clinical
studies will investigate if Rap1 signaling is altered in various pathologies, and whether there is interindividual
variability in this pathway in healthy and diseased subjects? Together, these studies are expected to lead to
novel strategies for the diagnosis and management of some inherited and acquired thrombocytopenias and
bleeding disorders, and to a more personalized approach to anti-platelet therapy.
抽象的
哺乳动物血小板是一种小型无核血细胞,专门用于持续监测和保存
心血管系统的完整性(止血)。它们由骨骼中的巨核细胞 (MK) 产生
骨髓并释放到血液中,它们在人类中循环十天,在小鼠中循环五天,直到它们
被吞噬细胞清除。血小板稳态,即建立明确的外周血小板计数,
需要严格调节血小板的产生和清除。为了发挥其止血功能,血小板
依赖于一种非常敏感的信号机制,可促进剪切应力下血小板的粘附。这个高
然而,敏感性会带来不必要的血小板活化的风险,从而导致血小板清除和/或
血栓形成。我们工作的总体目标是更好地了解分子
调节 MK 发育和血小板反应性的机制,特别关注小分子的作用
这些过程中的 GTP 酶。此 R35 OIA 申请是三项 NHLBI R01 拨款的延伸:
巨核细胞生物学中的小 GTP 酶; Rap1 信号在血小板稳态和血管止血中的作用;
Podoplanin-Clec2 信号传导对血小板激活的空间调节。我们的 MK 研究利用独特的
生物传感器,用于在过程中建立小 GTP 酶活性(Rho 和 Rap GTP 酶)的分子特征
发育的最后阶段,包括从增殖到前血小板形成的转变。一次
建立后,我们将建立原理验证,通过以下方式精确定位 GTPase 活性的扰动
光遗传学工具是优化体外血小板生成的可行策略,这是输血领域的热门话题
药品。我们的血小板工作更具体地关注 Rap GTPases 作为主要调节因子的作用
细胞活化和止血栓形成。我们利用独特的小鼠模型来建立
Rap1 信号在血小板激活过程中的重要性和关键调节因子。此外,我们还展示了
Rap1 活性必须在静态、循环和止血活性血小板中保持严格平衡,
该通路的紊乱会导致出血或血小板减少/血栓形成。在当前和未来
工作中,我们将扩展我们的细胞生物学和生化/物理研究,以提供全面的
了解 Rap 信号如何控制血小板功能、它是如何调节的以及它是否/如何有助于
其他病理生理过程,例如发育/炎症和静脉中的血管完整性
血栓形成。我们将使用我们独特的生化检测来筛选 Rap 信号传导抑制剂。我们的临床
研究将调查 Rap1 信号传导是否在各种病理学中发生改变,以及个体之间是否存在差异
健康和患病受试者中该途径的变异性?这些研究共同预计将导致
诊断和治疗一些遗传性和获得性血小板减少症的新策略
出血性疾病,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:
$ 84.21万 - 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:
$ 84.21万 - 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:
10676889 - 财政年份:2020
- 资助金额:
$ 84.21万 - 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:
$ 84.21万 - 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:
$ 84.21万 - 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:
$ 84.21万 - 项目类别:
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
- 批准号:
9330204 - 财政年份:2016
- 资助金额:
$ 84.21万 - 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:
$ 84.21万 - 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:
$ 84.21万 - 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:
$ 84.21万 - 项目类别:
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