Regulation of Weibel-Palade Body Secretion in AGA

AGA 中 Weibel-Palade 体分泌的调节

基本信息

  • 批准号:
    6739499
  • 负责人:
  • 金额:
    $ 34.83万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-04-01 至 2008-03-31
  • 项目状态:
    已结题

项目摘要

Accelerated graft arteriosclerosis (AGA) is the most common long-term cause of death in patients with cardiac allografts. AGA is characterized by a neointima of smooth muscle cells and macrophages in the arteries of transplanted organs. Although the pathogenesis of AGA is not completely understood, a variety of inducers--including complement, granzyme B, antibodies, and viral infections--may play a role in the process of inflammation and proliferation that ultimately leads to AGA. We and others have previously shown that nitric oxide (NO) inhibits AGA. In particular, NO derived from the inducible NO synthase (iNOS, or NOS2) appears to limit the vasculopathy that is a hallmark of AGA. For example, adenoviral delivery of NOS2 decreases AGA. In contrast, inhibitors of NOS increase AGA. Furthermore, genetic deletion of NOS2 exacerbates AGA: cardiac allografts develop more severe AGA when transplanted into NOS2 knockout mice, compared to hearts transplanted into wild-type mice. Thus NO derived from NOS2 protects cardiac allografts from AGA. The molecular mechanisms by which NO inhibits AGA are unknown. However, we recently discovered that NOS2 decreases inflammation in cardiac allografts. In particular, we found that NOS2 inhibits the release ot Weibel-Palade bodies from endothelial cells in donor hearts. Since Weibel-Palade bodies contain inflammatory and thrombotic mediators, inhibition of Weibel-Palade body release may explain part of the anti-inflammatory effects of NO in AGA and other vascular diseases. We now propose to explore the molecular mechanism by which NO inhibits Weibel-Palade body release. Preliminary Data shows that NO blocks Weibel-Palade body release from cultured endothelial cells. We will begin by determining whether or not NO can inhibit the triggering of Weibel-Palade body release by various inducers of AGA. Then we will define the mechanisms by which Weibel-Palade bodies are normally released. We will next determine the molecular targets of NO. Finally, we will examine the physiological relevance of these mechanisms in a murine model of AGA. These studies will characterize novel molecular mechanisms by which radicals regulate vascular inflammation.
加速性移植物动脉硬化(阿加)是心脏移植患者最常见的长期死亡原因。阿加的特征在于移植器官动脉中平滑肌细胞和巨噬细胞的新生内膜。虽然阿加的发病机制还没有完全了解,各种诱导剂-包括补体,颗粒酶B,抗体和病毒感染-可能在炎症和增殖过程中发挥作用,最终导致阿加。我们和其他人以前已经表明,一氧化氮(NO)抑制阿加。特别地,源自诱导型NO合酶(iNOS,或NOS 2)的NO似乎限制了作为阿加标志的血管病变。例如,NOS 2的腺病毒递送降低了阿加。相反,NOS抑制剂增加阿加。 此外,NOS 2的基因缺失会加重阿加:与移植到野生型小鼠的心脏相比,移植到NOS 2敲除小鼠的心脏同种异体移植物发生更严重的阿加。因此,NO衍生 保护心脏移植物免受阿加。NO抑制阿加的分子机制尚不清楚。然而,我们最近发现NOS 2可以减少心脏移植物中的炎症。特别是,我们发现NOS 2抑制了 供体心脏内皮细胞的韦伯-帕拉德小体。由于韦伯-帕拉德体含有炎症和血栓介质,抑制韦伯-帕拉德体释放可能解释了NO在阿加和其他血管疾病中的部分抗炎作用。 我们现在建议探索NO抑制韦伯-帕拉德体释放的分子机制。 初步数据显示,NO阻断了从培养的内皮细胞释放的韦伯-帕拉德体。我们将开始确定是否NO可以抑制触发的韦伯-帕拉德体释放的各种诱导剂的阿加。然后,我们将定义的机制,韦伯-帕拉德机构通常被释放。 接下来我们将确定NO的分子靶点。最后,我们将在阿加小鼠模型中研究这些机制的生理相关性。 这些研究将表征自由基调节血管炎症的新分子机制。

项目成果

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CHARLES J LOWENSTEIN其他文献

CHARLES J LOWENSTEIN的其他文献

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{{ truncateString('CHARLES J LOWENSTEIN', 18)}}的其他基金

Model system of oral contraceptive-induced VTE: integrating genomic, transcriptomic, and proteomic discovery with functional biology
口服避孕药诱发的 VTE 模型系统:将基因组学、转录组学和蛋白质组学发现与功能生物学相结合
  • 批准号:
    10418628
  • 财政年份:
    2020
  • 资助金额:
    $ 34.83万
  • 项目类别:
Model system of oral contraceptive-induced VTE: integrating genomic, transcriptomic, and proteomic discovery with functional biology
口服避孕药诱发的 VTE 模型系统:将基因组学、转录组学和蛋白质组学发现与功能生物学相结合
  • 批准号:
    10164668
  • 财政年份:
    2020
  • 资助金额:
    $ 34.83万
  • 项目类别:
Population genomic variation, functional biology, and the risk of venous thrombosis
群体基因组变异、功能生物学和静脉血栓形成的风险
  • 批准号:
    9750789
  • 财政年份:
    2017
  • 资助金额:
    $ 34.83万
  • 项目类别:
VAMP8 regulates endothelial exocytosis and microvascular obstruction
VAMP8 调节内皮胞吐作用和微血管阻塞
  • 批准号:
    8903561
  • 财政年份:
    2014
  • 资助金额:
    $ 34.83万
  • 项目类别:
Novel Regulators of Endothelial Exocytosis
内皮胞吐作用的新型调节剂
  • 批准号:
    8445932
  • 财政年份:
    2013
  • 资助金额:
    $ 34.83万
  • 项目类别:
Novel Regulators of Endothelial Exocytosis
内皮胞吐作用的新型调节剂
  • 批准号:
    8604406
  • 财政年份:
    2013
  • 资助金额:
    $ 34.83万
  • 项目类别:
Regulation of Exocytosis in the Post-Ischemic Myocardium
缺血后心肌胞吐作用的调节
  • 批准号:
    7160736
  • 财政年份:
    2006
  • 资助金额:
    $ 34.83万
  • 项目类别:
Exocytosis and Vascular Inflammation
胞吐作用和血管炎症
  • 批准号:
    7115398
  • 财政年份:
    2004
  • 资助金额:
    $ 34.83万
  • 项目类别:
Regulation of Vascular Inflammation
血管炎症的调节
  • 批准号:
    6889495
  • 财政年份:
    2004
  • 资助金额:
    $ 34.83万
  • 项目类别:
Exocytosis and Vascular Inflammation
胞吐作用和血管炎症
  • 批准号:
    6847671
  • 财政年份:
    2004
  • 资助金额:
    $ 34.83万
  • 项目类别:

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