aVB3 Activation and Phosphorylation in Angiogenesis

血管生成中的 aVB3 激活和磷酸化

基本信息

  • 批准号:
    6853213
  • 负责人:
  • 金额:
    $ 29.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-04-01 至 2009-03-31
  • 项目状态:
    已结题

项目摘要

The beta3 integrins mediate cellular functions that underlie a number of physiological and pathophysiological processes including angiogenesis which in turn are critical during atherosclerosis, myocardial injury, wound healing, tumor development and inflammatory diseases. Angiogenesis is triggered by interaction of vascular endothelial growth factors (VEGFs) with their receptors on endothelial cells which, in turn, leads to the cell activation and the changes of integrin functions. Despite an importance of the process of angiogenesis, its mechanisms are poorly understood. The overall objective of this proposal is to determine molecular mechanisms of communication between VEGFRs and alpha-v-beta3 integrin in angiogenesis and lymphangiogenesis. The major focus of this proposal is to assess the role of beta3 integrin cytoplasmic domain and its phosphorylation in the regulation of alpha-v-beta3 activity during the process of VEGF-induced angiogenesis, The elucidation of these mechanisms would create the basis for the development of novel therapeutic strategies in cardiology and vascular medicine. Proposed specific aims are: Aim I. To evaluate the role of beta3 integrin phosphorylation in VEGF-induced angiogenesis in vivo. The angiogenic responses will be assessed in mice expressing a mutated beta3 subunit that impairs its capacity to undergo tyrosine phosphorylation (DiYF) using matrigel and tumor-induced angiogenesis models. These studies will be complemented by unique adenovirus-induced subcutaneous and muscle models developed in our previous studies. We will compare responses initiated by different sets of VEGF receptors, VEGFR-2 and VEGFR-3, and we will utilize two VEGFs, VEGF-A165 and VEGF-D. Through these analyses, we will establish a physiological role of beta3 integrin phosphorylation and dissect how different communication pathways from VEGFRs to integrins influence angiogenesis. Aim II. To assess the molecular mechanism for the role of beta3 integrin phosphorylation in angiogenesis. In these studies we will utilize endothelial cells of different origin isolated from normal and DiYF mice. We will characterize the adhesive, migratory and proliferative responses of endothelial cells of different origin from normal and DiYF animals to VEGF as compared to other agonists. We will compare normal and DiYF endothelial cells for their ability to form capillary-like structures ex vitro. Aim III. To further determine the molecular requirements for beta3 integrin subunit to interact with VEGF receptors. In this set of studies, we will focus on the role of beta 3 cytoplasmic domain and its phosphorylation in the VEGF-induced functional responses. We will assess whether beta3 integrin phosphorylation plays a role in VEGF-induced integrin activation. The role of specific intermediates in the signal transduction from different VEGFRs will be considered (including role of talin and skelemin in VEGFRs-induced activation).
β 3整联蛋白介导的细胞功能是许多生理和病理生理过程的基础,包括血管生成,而血管生成又在动脉粥样硬化、心肌损伤、伤口愈合、肿瘤发展和炎性疾病中至关重要。血管生成是由血管内皮生长因子(vascular endothelial growth factors,VEGFs)与内皮细胞上的受体相互作用而触发的,进而导致细胞活化和整合素功能的改变。尽管血管生成过程的重要性,其机制知之甚少。该建议的总体目标是确定血管生成和淋巴管生成中VEGF和α-v-β 3整联蛋白之间的通讯的分子机制。本研究的主要目的是探讨β 3整合素胞浆结构域及其磷酸化在VEGF诱导血管生成过程中对α-v-β 3活性的调节作用,阐明其作用机制将为心血管疾病治疗策略的发展奠定基础。拟议的具体目标是:评价β 3整合素磷酸化在VEGF诱导的体内血管生成中的作用。将使用基质胶和肿瘤诱导的血管生成模型,在表达突变的β 3亚基的小鼠中评估血管生成反应,所述突变的β 3亚基损害其进行酪氨酸磷酸化(DiYF)的能力。这些研究将补充独特的腺病毒诱导的皮下和肌肉模型 在我们以前的研究中。我们将比较由不同组的VEGF受体VEGFR-2和VEGFR-3引发的反应,并且我们将利用两种VEGF VEGF-A165和VEGF-D。通过这些分析,我们将建立β 3的生理作用, 整合素磷酸化,并剖析从VEGF到整合素的不同通讯途径如何影响血管生成。Aim II.评估β 3整合素磷酸化在血管生成中作用的分子机制。在这些研究中,我们将利用从正常和DiYF小鼠分离的不同来源的内皮细胞。我们将表征与其他激动剂相比,来自正常和DiYF动物的不同来源的内皮细胞对VEGF的粘附、迁移和增殖反应。我们将比较正常和DiYF内皮细胞体外形成毛细血管样结构的能力。Aim III.进一步确定β 3整联蛋白亚基与VEGF受体相互作用的分子要求。在这组研究中,我们将集中在β 3胞浆结构域及其磷酸化在VEGF诱导的功能反应中的作用。我们将评估β 3整合素磷酸化是否在VEGF诱导的整合素活化中起作用。信号中特定中间体的作用 将考虑来自不同VEGF的转导(包括talin和talemin在VEGF诱导的活化中的作用)。

项目成果

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Tatiana V Byzova其他文献

Tatiana V Byzova的其他文献

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{{ truncateString('Tatiana V Byzova', 18)}}的其他基金

Role of TLR2 in angiogenesis
TLR2 在血管生成中的作用
  • 批准号:
    10377903
  • 财政年份:
    2019
  • 资助金额:
    $ 29.65万
  • 项目类别:
Platelets in Cancer
癌症中的血小板
  • 批准号:
    10199008
  • 财政年份:
    2018
  • 资助金额:
    $ 29.65万
  • 项目类别:
AlphaVbetaIII Activation in Blood and Endothelial Cells in Angiogenesis
血管生成过程中血液和内皮细胞中的 AlphaVbetaIII 激活
  • 批准号:
    8378029
  • 财政年份:
    2004
  • 资助金额:
    $ 29.65万
  • 项目类别:
AlphaVbetaIII Activation in Blood and Endothelial Cells in Angiogenesis
血管生成过程中血液和内皮细胞中的 AlphaVbetaIII 激活
  • 批准号:
    8069593
  • 财政年份:
    2004
  • 资助金额:
    $ 29.65万
  • 项目类别:
AlphaVbetaIII Activation in Blood and Endothelial Cells in Angiogenesis
血管生成过程中血液和内皮细胞中的 AlphaVbetaIII 激活
  • 批准号:
    7657893
  • 财政年份:
    2004
  • 资助金额:
    $ 29.65万
  • 项目类别:
AlphaVbetaIII Activation in Blood and Endothelial Cells in Angiogenesis
血管生成过程中血液和内皮细胞中的 AlphaVbetaIII 激活
  • 批准号:
    8260296
  • 财政年份:
    2004
  • 资助金额:
    $ 29.65万
  • 项目类别:
Project 3 Function of Kindlin-3 in blood and endothelial cells
项目3 Kindlin-3在血液和内皮细胞中的功能
  • 批准号:
    9069122
  • 财政年份:
    2004
  • 资助金额:
    $ 29.65万
  • 项目类别:
AlphaVbetaIII Activation in Blood and Endothelial Cells in Angiogenesis
血管生成过程中血液和内皮细胞中的 AlphaVbetaIII 激活
  • 批准号:
    8468200
  • 财政年份:
    2004
  • 资助金额:
    $ 29.65万
  • 项目类别:
Integrins and bone matrix in prostate cancer
前列腺癌中的整合素和骨基质
  • 批准号:
    6708390
  • 财政年份:
    2003
  • 资助金额:
    $ 29.65万
  • 项目类别:
Activation of alpha5beta3 integrin on blood and endothelial cells
血液和内皮细胞上 α5β3 整合素的激活
  • 批准号:
    7253409
  • 财政年份:
    2003
  • 资助金额:
    $ 29.65万
  • 项目类别:

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  • 批准号:
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  • 财政年份:
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