Regulation and function of PDK1-Akt-Pyk2 axis in platelets
血小板 PDK1-Akt-Pyk2 轴的调节和功能
基本信息
- 批准号:9088501
- 负责人:
- 金额:$ 47.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-08-01 至 2017-11-30
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAffectAgonistBiochemicalBlood PlateletsCellsClot retractionComplexCytoplasmic GranulesDataEventFibrinogenFibrinogen ReceptorsG-Protein Signaling PathwayGTP-Binding ProteinsGenerationsHealthHemostatic functionIntegrinsKineticsKnockout MiceLeadMediatingMembraneMolecular GeneticsMusPTK2B genePathway interactionsPhosphatidylinositide 3-Kinase InhibitorPhosphatidylinositolsPhosphorylationPhosphotransferasesPhysiologicalPlatelet ActivationPlayProteinase-Activated ReceptorsProto-Oncogene Proteins c-aktReceptor ActivationRegulationRoleShapesSignal PathwaySignal TransductionSignaling MoleculeSurfaceSystemTestingThrombinThrombosisThromboxane A2Thromboxane ReceptorThromboxanesTyrosine PhosphorylationWorkgenetic approachinhibitor/antagonistknockout genep21 activated kinasereceptorresponsesrc-Family Kinases
项目摘要
DESCRIPTION (provided by applicant): Platelet activation plays a major role in hemostasis and thrombosis. Platelet agonists activate complex signaling cascades resulting in shape change, aIIbb3 integrin activation, and dense granule release and thromboxane A2 (TXA2) generation, amplifying the initial signal. The signaling cascades and the intracellular interaction of these signaling molecules regulating platelet physiological events have not been completely understood. In this application, we propose to test the overall hypothesis that PDK1-Akt-Pyk2 axis regulates platelet functional responses. We propose to understand the interaction of these signaling molecules and the downstream events in the agonist-induced platelet activation using complimentary biochemical, pharmacological, and gene knockout approaches. PDK1 is known to phosphorylate a number of kinases, but its function in platelets has not been elucidated. Aim 1) We hypothesize that PDK1 plays an important positive regulatory role in platelets through selective phosphorylation and activation of Akt. We propose to test this hypothesis through selective pharmacological inhibitors of PDK1 and using conditional PDK1 null mice. Our preliminary data shows that PDK1 phosphorylation of Thr308 is crucial for the activity of Akt and downstream signaling events. Furthermore our preliminary data shows that PDK1 inhibition affects agonist-induced platelet integrin activation and TXA2 generation. Aim 2) We hypothesize that intracellular association of PAK with Akt is crucial for its phosphorylation by PDK1. We propose to evaluate the role of PAK in translocation of Akt to the membrane using pharmacological approaches and PAK1 and 2 knockout mice. In preliminary data, we show that Akt translocation to the membrane and phosphorylation follows different kinetics. We postulate that PYK2, through tyrosine phosphorylation of PI3 kinases and PDK1, regulates platelet functional responses and Akt phosphorylation. We also postulate that Pyk2 is activated by G12/13 pathways and regulates thromboxane generation. We will evaluate the function of Pyk2 in aIIbb3 integrin activation, TXA2 generation, clot retraction, and spreading on immobilized fibrinogen, using knockout mice and pharmacological inhibitors. Our preliminary data shows that Pyk2 plays an important role in these platelet functional responses. These studies will enhance our understanding of the intracellular interactions of signaling molecules and their role in platelet activation, and might identify potential newer targets for the treatmentof thrombosis.
描述(由申请方提供):血小板活化在止血和血栓形成中起主要作用。血小板激动剂激活复杂的信号级联,导致形状改变、aIIbb 3整联蛋白激活、致密颗粒释放和血栓烷A2(TXA 2)产生,放大初始信号。这些信号分子调节血小板生理事件的信号级联和细胞内相互作用尚未完全了解。在本申请中,我们提出测试PDK 1-Akt-Pyk 2轴调节血小板功能反应的总体假设。我们建议了解这些信号分子的相互作用和下游事件中的激动剂诱导的血小板活化使用互补的生化,药理学和基因敲除的方法。已知PDK 1磷酸化许多激酶,但其在血小板中的功能尚未阐明。目的1)我们推测PDK 1通过选择性磷酸化和激活Akt对血小板起重要的正性调节作用。我们建议通过PDK 1的选择性药理学抑制剂和使用条件性PDK 1无效小鼠来测试这一假设。我们的初步数据表明,Thr 308的PDK 1磷酸化对于Akt的活性和下游信号事件至关重要。此外,我们的初步数据显示,PDK 1抑制影响激动剂诱导的血小板整合素活化和TXA 2生成。目的2)我们假设PAK与Akt的细胞内结合对于其被PDK 1磷酸化是至关重要的。我们建议使用药理学方法和PAK 1和2基因敲除小鼠来评估PAK在Akt易位到膜中的作用。在初步数据中,我们表明Akt易位到膜和磷酸化遵循不同的动力学。我们推测PYK 2通过PI 3激酶和PDK 1的酪氨酸磷酸化调节血小板功能反应和Akt磷酸化。我们还假设Pyk 2被G12/13通路激活并调节血栓素的产生。我们将使用基因敲除小鼠和药理学抑制剂评估Pyk 2在aIIbb 3整合素活化、TXA 2生成、凝块收缩和在固定纤维蛋白原上扩散中的功能。我们的初步数据表明Pyk 2在这些血小板功能反应中起着重要作用。这些研究将增强我们对信号分子的细胞内相互作用及其在血小板活化中的作用的理解,并可能为血栓形成的治疗确定潜在的新靶点。
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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Satya P. Kunapuli其他文献
The Third Extracellular Loop of the μ Opioid Receptor Is Important for Agonist Selectivity
- DOI:
10.1016/s0021-9258(18)92233-7 - 发表时间:
1995-06-02 - 期刊:
- 影响因子:
- 作者:
Ji-Chun Xue;Chongguang Chen;Jinmin Zhu;Satya P. Kunapuli;J. Kim de Riel;Lei Yu;Lee-Yuan Liu-Chen - 通讯作者:
Lee-Yuan Liu-Chen
Satya P. Kunapuli的其他文献
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{{ truncateString('Satya P. Kunapuli', 18)}}的其他基金
Novel signaling molecules regulating platelet activation
调节血小板活化的新型信号分子
- 批准号:
10851106 - 财政年份:2023
- 资助金额:
$ 47.41万 - 项目类别:
Novel signaling molecules regulating platelet activation
调节血小板活化的新型信号分子
- 批准号:
10611919 - 财政年份:2021
- 资助金额:
$ 47.41万 - 项目类别:
Novel signaling molecules regulating platelet activation
调节血小板活化的新型信号分子
- 批准号:
10393576 - 财政年份:2021
- 资助金额:
$ 47.41万 - 项目类别:
Regulation and function of PDK1-Akt-Pyk2 axis in platelets
血小板 PDK1-Akt-Pyk2 轴的调节和功能
- 批准号:
8707878 - 财政年份:2013
- 资助金额:
$ 47.41万 - 项目类别:
Regulation and function of PDK1-Akt-Pyk2 axis in platelets
血小板 PDK1-Akt-Pyk2 轴的调节和功能
- 批准号:
8876781 - 财政年份:2013
- 资助金额:
$ 47.41万 - 项目类别:
Regulation and function of PDK1-Akt-Pyk2 axis in platelets
血小板 PDK1-Akt-Pyk2 轴的调节和功能
- 批准号:
8580272 - 财政年份:2013
- 资助金额:
$ 47.41万 - 项目类别:
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