Novel Roles for Phosphoinositide Signaling in alpha-Granule Biogenesis
磷酸肌醇信号传导在 α 颗粒生物发生中的新作用
基本信息
- 批准号:9884351
- 负责人:
- 金额:$ 11.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-01 至 2020-08-17
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAlpha GranuleBindingBinding ProteinsBiochemicalBiogenesisBiologyBloodBlood CellsBlood PlateletsBlood coagulationBone MarrowCell membraneCellsCollaborationsCytoplasmCytoplasmic GranulesDataDefectDevelopmentEnvironmentFatty AcidsGOLPH3 geneGolgi ApparatusGrowth FactorHandHematopoiesisHematopoietic stem cellsHumanHydrophobicityImpairmentIndianaIndividualInflammationKnock-outLeftLinkMaintenanceMediatingMegakaryocytesMegakaryocytopoiesesMembraneMorphologyMultivesicular BodyMusMutateMutationMyocardial InfarctionNeuronsPatientsPhenotypePhosphatidylinositol Transfer ProteinPhosphatidylinositolsPhospholipidsPlatelet ActivationPlayProcessProductionPropertyProtein FamilyProtein IsoformsProteinsPublicationsPublishingRegulationRoleSecond Messenger SystemsSignal PathwaySignal TransductionStrokeSyndromeTestingThrombosisTransforming Growth Factor betaTransmembrane TransportUniversitiesaqueouscytokinehuman diseasein vivomembermonomernovelprotein transportrecruittraffickingtrans-Golgi Network
项目摘要
Project Summary
Phosphorylated phosphatidylinositols (phosphoinositides) are a type of membrane bound
phospholipid that impact multiple diverse processes required for megakaryopoiesis and the
activation of platelets. We have recently published in Developmental Cell that phosphoinositides
in neuronal cells initiate intracellular trafficking by recruiting effector proteins such as GOLPH3
that are involved in vesicular fusion and budding of plasma membranes during Golgi biogenesis.
Since megakaryocyte α-granules are derived from the trans-Golgi network and Multi-Vesicular
Bodies, I hypothesize that phosphoinositide signaling is necessary for the intracellular trafficking
required for the biogenesis of α-granules. PhosphatidylInositol Transfer Proteins (PITPs) are
members of a small protein family that bind and transfer phosphoinositide monomers from one
cellular compartment to another and thereby enable phosphoinositide synthesis. We have made
the unexpected observation that the two predominant PITP isoforms found within
megakaryocytes, PITPα and PITPβ play previously unrecognized but essential roles in the
trafficking of cargo from the Multi-Vesicular Body to α-granules. Loss of PITP-mediated
phosphoinositide synthesis produces morphologic defects similar to what is seen in humans with
Gray Platelet Syndrome. The overall hypothesis of this Proposal is that phosphoinositide signaling
mediated by PITPs is necessary for the membrane dynamics and protein trafficking required for
the biogenesis and maintenance of megakaryocyte α-granules. In Aim 1 of the Project, we will
rigorously analyze the discrete biochemical properties of individual PITP isoforms in
megakaryocytes. Our preliminary data shows that the two PITP isoforms control phosphoinositide
signaling through biochemically distinct mechanisms. In Aim 2, we will determine how
phosphoinositide signaling contributes to alpha granule biogenesis and function. We will test the
hypothesis that phosphoinositide synthesis within discrete microdomains of megakaryocytes and
platelets regulates effector proteins such as NBEAL2 (the mutated protein responsible for Gray
Platelet Syndrome). This signaling cascade modulates NBEAL2’s ability to mediate membrane
dynamics and protein trafficking. We will also analyze in detail the functional roles of α-granules
with ex vivo rheologic and ultramicroscopy studies, in vivo thrombosis studies, and in vivo
inflammation studies.
项目摘要
磷酸化磷脂酰肌醇(磷酸肌醇)是一种膜结合型磷脂酰肌醇。
磷脂影响巨核细胞生成所需的多种不同过程,
激活血小板。我们最近在《发育细胞》上发表了磷酸肌醇
在神经元细胞中通过募集效应蛋白如GOLPH 3启动细胞内运输
它们参与高尔基体生物发生过程中质膜的泡状融合和出芽。
由于巨核细胞α-颗粒来源于高尔基体网络和多囊泡细胞,
因此,我假设磷酸肌醇信号传导对于细胞内运输是必要的
是α颗粒生物发生所必需的。磷脂酰肌醇转移蛋白(PITP)是
一个小的蛋白质家族的成员,结合和转移磷酸肌醇单体从一个
细胞隔室彼此相连,从而使磷酸肌醇合成成为可能。我们取得了
出乎意料的观察结果是,在细胞内发现的两种主要的PITP同种型,
在巨核细胞中,PITPα和PITPβ发挥着以前未被认识到的但重要的作用,
将货物从多囊泡体运输到α颗粒。PITP介导的丢失
磷酸肌醇合成产生的形态缺陷类似于在人类中观察到的,
灰色血小板综合征。该提案的总体假设是磷酸肌醇信号传导
由PITP介导的是必要的膜动力学和蛋白质运输所需的
巨核细胞α颗粒的生物发生和维持。在项目目标1中,我们将
严格分析单个PITP亚型的离散生化特性,
巨核细胞我们的初步数据表明,两个PITP亚型控制磷酸肌醇
通过生物化学上不同的机制发出信号。在目标2中,我们将确定如何
磷酸肌醇信号传导有助于α颗粒生物发生和功能。我们将测试
巨核细胞离散微区内磷酸肌醇合成
血小板调节效应蛋白,如NBEAL 2(负责Gray的突变蛋白),
血小板综合征)。这种信号级联调节NBEAL 2介导膜粘附的能力。
动力学和蛋白质运输。我们还将详细分析α颗粒的功能作用
离体流变学和超显微镜研究、体内血栓形成研究和体内
炎症研究。
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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CHARLES S. ABRAMS其他文献
CHARLES S. ABRAMS的其他文献
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{{ truncateString('CHARLES S. ABRAMS', 18)}}的其他基金
The Novel Mechanisms of Thrombosis Formation in Myeloproliferative Diseases
骨髓增生性疾病血栓形成的新机制
- 批准号:
10424485 - 财政年份:2020
- 资助金额:
$ 11.01万 - 项目类别:
The Novel Mechanisms of Thrombosis Formation in Myeloproliferative Diseases
骨髓增生性疾病血栓形成的新机制
- 批准号:
10187644 - 财政年份:2020
- 资助金额:
$ 11.01万 - 项目类别:
Novel Roles for Phosphoinositide Signaling in alpha-Granule Biogenesis
磷酸肌醇信号传导在 α 颗粒生物发生中的新作用
- 批准号:
10656287 - 财政年份:2020
- 资助金额:
$ 11.01万 - 项目类别:
The Novel Mechanisms of Thrombosis Formation in Myeloproliferative Diseases
骨髓增生性疾病血栓形成的新机制
- 批准号:
10627990 - 财政年份:2020
- 资助金额:
$ 11.01万 - 项目类别:
Novel Roles for Phosphoinositide Signaling in alpha-Granule Biogenesis
磷酸肌醇信号传导在 α 颗粒生物发生中的新作用
- 批准号:
10161821 - 财政年份:2020
- 资助金额:
$ 11.01万 - 项目类别:
Novel Roles for Phosphoinositide Signaling in alpha-Granule Biogenesis
磷酸肌醇信号传导在 α 颗粒生物发生中的新作用
- 批准号:
10434809 - 财政年份:2020
- 资助金额:
$ 11.01万 - 项目类别:
Platelet signals and their interface with the external environment
血小板信号及其与外部环境的接口
- 批准号:
8909166 - 财政年份:2014
- 资助金额:
$ 11.01万 - 项目类别:
Platelet signals and their interface with the external environment
血小板信号及其与外部环境的接口
- 批准号:
8742306 - 财政年份:2014
- 资助金额:
$ 11.01万 - 项目类别:
Platelet signals and their interface with the external environment
血小板信号及其与外部环境的接口
- 批准号:
9315871 - 财政年份:2014
- 资助金额:
$ 11.01万 - 项目类别:
The Biological Roles of Phoshadylinositol Transfer Proteins in Platelets
血小板中磷脂肌醇转移蛋白的生物学作用
- 批准号:
8257824 - 财政年份:2012
- 资助金额:
$ 11.01万 - 项目类别:
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