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REGULATION OF ENDOTHELIAL CELL ECTO-ADPASE ACTIVITY

REGULATION OF ENDOTHELIAL CELL ECTO-ADPASE ACTIVITY
内皮细胞胞外 ADP 酶活性的调节
批准号:
6202312
负责人:
Aaron Jacob Marcus
金额:
$28.8万
依托单位国家:
美国
项目类别:
财政年份:
1999
资助国家:
美国
项目状态:
已结题
起止时间:
1999-08-01 至 2000-07-31

项目摘要

项目成果

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中文摘要
翻译
我们实验室最近的研究导致了内皮细胞的概念 细胞血栓调节。血管引起的血小板活化 损伤导致内皮细胞(EC)以定向方式做出反应 限制或逆转血小板的闭塞后果 积累。这种限制或逆转是由EC通过3 独立的血栓调节系统:内皮来源的二十烷基类化合物 松弛因子(EDRF/NO),最重要的是,内皮细胞外膜- 核苷酸酶。后者迅速代谢血小板释放的ADP 从而使血小板恢复到静息状态。建议进行的研究 该项目将侧重于控制系统和机制,负责 血管血栓调节的调节。主要重点将放在 自我们之前的研究以来,关于内皮细胞胞外-ADPase活性的研究 突出了这个酶系统。为此,我们将确定机制 白介素1b、肿瘤坏死因子-α、干扰素-g和白介素13等细胞因子通过哪些途径调节 ADPase活性和基因表达。此外,我们还将评估 5‘-亚基对EC ecto-ADPase转录调控的研究 调控区域,包括细胞因子反应元件。我们的 与项目II的协作将是成功完成 这些目标,因为K.Hajjar博士和D.Hajjar博士在这一领域拥有专业知识 研究的成果。由于EC的初步研究表明IL-13可诱导 Janus Kinase Jak-2的磷酸化,我们将研究IL-2是否 13 EC ADPase活性上调与JAK-1激活有关 信号转导的STAT通路。我们与Project IV的合作 将对实现这些目标至关重要,因为亨普斯特德博士已经 在这一发展中的学科中拥有相当多的专业知识。对中国传统文化的研究 双脂氧合酶产物脂氧素A4的抗血栓作用 将被扩展以评估其上调EC ADPase的能力 活动。此外,确定LXA4是否可以 预防或逆转血栓形成前EC ADPase活性下调 由细胞因子暴露引起的。为了进一步阐明的功能 LXA4作为一种抗血栓的二十烷类化合物,我们将分离出EC特异性的LXA4 受体c DNA,使用我们最近的全开放阅读框架(ORF) 获得髓系LXA4受体作为探针。EC特异性LXA4受体 然后在哺乳动物身上进行生化和功能鉴定 表达系统(S)。波梅兰茨博士和D.Hajjar博士在 二十烷类分子生物学将是实现这些目标的关键。 对EC ADPase活性控制机制的理解可能会导致 合理有效的抗血栓治疗形式的发展 可以在血栓形成的最早阶段实施。
英文摘要
Recent research in our laboratory has led to the concept of endothelial cell Thromboregulation. Platelet activation as a consequence of vascular injury causes endothelial cells (EC) to respond in a manner directed toward limitation or reversal of the occlusive consequences of platelet accumulation. Such limitation or reversal is achieved by EC via 3 separate Thromboregulatory systems: Eicosanoids, endothelium-derived relaxing factor (EDRF/NO), and, most importantly, an endothelial ecto- nucleotidase. The latter rapidly metabolizes platelet-released ADP thereby restoring platelets to the resting state. Research proposed in this project will focus on control systems and mechanisms responsible for modulation of vascular Thromboregulation. Major emphasis will be placed on endothelial ecto-ADPase activity since our previous research has highlighted this enzyme system. To this end we will determine mechanisms by which cytokines, such as IL-1b, TNF-a, IFN-g, and IL-13, regulate ADPase activity and gene expression. In addition, we will assess transcriptional regulation of EC ecto-ADPase by elements of the 5'- regulatory region, including cytokine response elements. Our collaborations with Project II will be crucial to successful completion of these aims, since Drs. K. Hajjar and D. Hajjar have expertise in this area of research. Since preliminary studies in EC indicated that IL-13 induces phosphorylation of the Janus kinase Jak-2, we will investigate whether IL- 13 upregulation of EC ADPase activity is related to activation of the Jak- STAT pathway of signal transduction. Our collaboration with Project IV will be essential for achieving these objectives, since Dr. Hempstead has considerable expertise in this developing discipline. Studies of the antithrombotic function of the double lipoxygenase product, lipoxin A4, will be extended to evaluate its capacity for upregulation of EC ADPase activity. Furthermore, it will be important to determine whether LXA4 can prevent or reverse the prothrombotic downregulation of EC ADPase activity resulting from cytokine exposure. To further elucidate the function of LXA4 as an antithrombotic eicosanoid, we will isolate the EC-specific LXA4 receptor cDNA, using the full open reading frame (ORF) of our recently obtained myeloid LXA4 receptor as a probe. The EC-specific LXA4 receptor will then be biochemically and functionally characterized in mammalian expression system(s). The expertise of Drs. Pomerantz and D. Hajjar in eicosanoid molecular biology will be essential for achieving these aims. An understanding of mechanisms controlling EC ADPase activity may lead to development of rational effective forms of antithrombotic therapy which can be implemented at the very earliest stages of thrombus formation.
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Thromboregulation by Endothelial Cells: Role of CD39
  • 批准号:
    8540643
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2013
  • 负责人:
    Aaron Jacob Marcus
  • 依托单位:
Thromboregulation by Endothelial Cells: Role of CD39
  • 批准号:
    8824829
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2013
  • 负责人:
    Aaron Jacob Marcus
  • 依托单位:
Thromboregulation in Occlusive Vascular Diseases
Thromboregulation in Occlusive Vascular Diseases
海外基金