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:
    10656287
  • 负责人:
  • 金额:
    $ 50.45万
  • 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:
    2020-05-10 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

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. In conjunction with Project 2, 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 the 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 that will be performed with Project 2, in vivo thrombosis studies with Project 3, and in vivo inflammation studies with Project 4.
磷酸化磷脂酰肌醇(磷酸肌醇)是一种膜结合蛋白 磷脂影响巨核细胞生成和巨核细胞生成所需的多种不同过程 血小板的活化。我们最近在《发育细胞》上发表了磷酸肌醇 在神经元细胞中,通过招募 GOLPH3 等效应蛋白来启动细胞内运输 在高尔基体生物发生过程中参与囊泡融合和质膜出芽。 由于巨核细胞 α 颗粒源自跨高尔基体网络和多囊泡 身体,我假设磷酸肌醇信号对于细胞内运输是必需的 α-颗粒的生物发生所必需的。磷脂酰肌醇转移蛋白 (PITP) 是 一个小蛋白质家族的成员,可结合并转移磷酸肌醇单体 细胞区室相互连接,从而实现磷酸肌醇的合成。我们已经做了 意外的观察发现,两种主要的 PITP 亚型在 巨核细胞、PITPα 和 PITPβ 在 将货物从多囊泡体贩运到 α 颗粒。 PITP介导的丧失 磷酸肌醇合成会产生与人类中所见相似的形态缺陷 灰血小板综合症。该提案的总体假设是磷酸肌醇信号传导 PITP 介导的膜动力学和蛋白质运输是必要的 巨核细胞α颗粒的生物发生和维持。在该项目的目标 1 中,我们将 严格分析单个 PITP 异构体的离散生化特性 巨核细胞。我们的初步数据表明,两种 PITP 亚型控制磷酸肌醇 通过不同的生化机制发出信号。在目标 2 中,我们将确定如何 磷酸肌醇信号传导有助于α颗粒的生物发生和功能。结合 在项目 2 中,我们将测试以下假设:离散的磷酸肌醇合成 巨核细胞和血小板的微结构域调节效应蛋白,例如 NBEAL2( 导致灰血小板综合症的突变蛋白)。该信号级联调节 NBEAL2 介导膜动力学和蛋白质运输的能力。我们还将分析在 通过离体流变学和超显微镜研究详细说明 α-颗粒的功能作用 将与项目 2 一起进行,体内血栓形成研究与项目 3 一起进行,以及体内炎症研究 研究项目 4。

项目成果

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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:
    $ 50.45万
  • 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:
    $ 50.45万
  • 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:
    9884351
  • 财政年份:
    2020
  • 资助金额:
    $ 50.45万
  • 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:
    $ 50.45万
  • 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:
    $ 50.45万
  • 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:
    $ 50.45万
  • 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:
    $ 50.45万
  • 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:
    $ 50.45万
  • 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:
    $ 50.45万
  • 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:
    $ 50.45万
  • 项目类别:

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