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COX-2 Mediated Inflammation of Cerebral Blood Vessels

COX-2 Mediated Inflammation of Cerebral Blood Vessels
COX-2介导的脑血管炎症
批准号:
6529750
负责人:
JOHNNY E BRIAN
金额:
$29.4万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2001
资助国家:
美国
项目状态:
已结题
起止时间:
2001-09-30 至 2003-08-31

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中文摘要
翻译
描述(由申请人提供):本申请的总体目标 是为脑血管张力调节的变化提供新的见解 脑损伤后。具体而言,拟议的研究将调查 有助于大脑小动脉延迟扩张的机制, 在短暂暴露于急性血管扩张剂缓激肽或花生四烯酸 酸在脑内,缓激肽和花生四烯酸都能产生急性、可逆的 由活性氧介导的血管舒张,最可能是氢 过氧化物在离体组织和细胞中发现了活性氧 引起环氧合酶-2(考克斯-2)的表达, 环氧合酶我们假设大脑短暂暴露于缓激肽 或花生四烯酸产生延迟的血管舒张,其在数小时后发生。 我们还假设,这种延迟的血管舒张几乎是由 仅通过考克斯-2,其表达被活性氧上调 物种本申请中提出的研究将使用颅骨窗 麻醉大鼠模型。颅窗提供了独特的研究能力 大脑循环中的脑组织仍然完整。初始 研究将进行系统的探索浓度-和 急性暴露产生的延迟扩张的时间依赖性 缓激肽或花生四烯酸。后续研究将使用药理学 拮抗剂,以确定考克斯-2和诱导型NO合酶在 延迟性血管舒张。免疫组织化学研究将验证表达 并通过使用考克斯-2蛋白鉴定表达考克斯-2的细胞类型。 共聚焦显微镜双标记。最后一系列项目将 研究活性氧在缓激肽和花生四烯酸 酸介导的考克斯-2表达延迟。氢的特殊作用 过氧化氢将被调查,以及过氧化氢的能力, 以诱导延迟的、考克斯-2依赖性扩张。 这些研究将在大脑中引入一个重要的新概念 急性扩张剂如缓激肽和花生四烯酸可以 引起基因表达的变化,这是延迟血管效应的基础。
英文摘要
DESCRIPTION (provided by the applicant): The overall goal of this application is to provide new insight into changes in the regulation of brain vascular tone following brain injury. Specifically, the proposed studies will investigate the mechanisms that subserve the delayed dilatation of brain arterioles that occurs after transient exposure to the acute vasodilators bradykinin or arachidonic acid. In brain, both bradykinin and arachidonic acid produce acute, reversible vasodilatation mediated by reactive oxygen species, most likely hydrogen peroxide. Reactive oxygen species have been shown in isolated tissues and cells to cause expression of cyclooxygenase-2 (COX-2), an inducible isoform of cyclooxygenase. We hypothesize that transient exposure of brain to bradykinin or arachidonic acid produces a delayed vasodilatation that occurs hours later. We also hypothesize that this delayed vasodilatation is mediated almost exclusively by COX-2, whose expression is upregulated by reactive oxygen species. The studies proposed in this application will use a cranial window model in anesthetized rats. Cranial windows offer the unique ability to study the cerebral circulation where it remains integrated brain tissue. Initial studies will undertake a systematic exploration of the concentration- and time-dependence of the delayed dilatation produced by acute exposure to bradykinin or arachidonic acid. Subsequent studies will use pharmacologic antagonists to establish the role of COX-2 and inducible NO-synthase in the delayed vasodilatation. Immunohistochemical studies will verify the expression of COX-2 protein and also identify the cell type expressing COX-2 by use of double labeling with confocal microscopy. The final series of projects will investigate the role of reactive oxygen species in bradykinin- and arachidonic acid-mediated delayed expression of COX-2. The specific role of hydrogen peroxide will be investigated, as well as the ability of hydrogen peroxide alone to induce delayed, COX-2 dependent dilatation. These studies will introduce an important new concept in the cerebral circulation - that acute dilators such as bradykinin and arachidonic acid can cause changes in gene expression that underlie delayed vascular effects.
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COX2 Mediated Inflammation of Cerebral Blood Vessels
  • 批准号:
    6416487
  • 项目类别:
  • 资助金额:
    $29.26万
  • 财政年份:
    2001
  • 负责人:
    JOHNNY E BRIAN
  • 依托单位:
海外基金