Regulation and function of EC-SOD

EC-SOD的调节和功能

基本信息

  • 批准号:
    7150859
  • 负责人:
  • 金额:
    $ 38.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2000
  • 资助国家:
    美国
  • 起止时间:
    2000-09-01 至 2007-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Extracellular superoxide dismutase (EC-SOD) is the most abundant extracellular antioxidant enzyme in the lung and current studies indicates that EC-SOD plays a key role in the pathogenesis of oxidant-induced pulmonary and vascular injury and resulting inflammation. We and others have shown that EC-SOD overexpression in the lungs of mice protects the lungs against acute lung injury from hyperoxia exposure, residual oil fly ash, influenza pneumonia, hemorrhage induced lung injury, radiation pneumonitis, bleomycin-induced lung fibrosis and preserves lung development in a neonatal model of hyperoxia. In cardiovascular disease models, EC-SOD protects against ischemia-reperfusion injury, attenuates hypertension, and specific polymorphisms impart a significant increased risk for ischemic heart disease. Despite this work, the precise mechanism of EC-SOD's protective role in these disease processes remains unclear. Recently we have begun to unravel factors important in regulating EC-SOD tissue and cell-specific expression. In this competing renewal application, we will build on our most recent findings that have begun to explore molecular pathways that control EC-SOD gene expression. Based on our initial characterization of the human and mouse EC-SOD genes, we now hypothesize that EC-SOD transcriptional expression is regulated by a family of transcription factors (Ets, MZF-1, Kruppel, and Sp1/Sp3) interacting at a proximal and distal promoter element located in the 5'-untranslated region of the murine EC-SOD gene. It is further proposed that the activity of these elements is modulated by epigenetic processes including histone acetylation and methylation. To test these hypotheses, we propose 3 specific aims. Aim 1 will examine the contribution and identification of cis-elements and trans-activating factors regulating basal and cell specific EC-SOD expression in the lung. In Aim 2, we will identify and characterize transcription factor elements responsible for modulation of EC-SOD gene transcription. In Aim 3 will use a novel in vivo bioluminescence imaging system to examine the functional and spatial gene expression profile utilizing the newly discovered EC-SOD proximal and distal promoter elements in transgenic mice. It is anticipated that this work will provide new insights into our understanding of molecular mechanisms involved in the regulation of EC-SOD gene expression. This could lead to novel pharmacologic strategies for augmenting endogenous EC-SOD levels in the lungs and other tissues, which would be predicted to reduce extracellular oxidative stress and attenuate lung disease processes.
描述(由申请人提供):细胞外超氧化物歧化酶(EC-SOD)是肺中最丰富的细胞外抗氧化酶,目前的研究表明,EC-SOD在氧化剂诱导的肺和血管损伤以及导致的炎症的发病机制中起关键作用。我们和其他人已经表明,小鼠肺中的EC-SOD过表达保护肺免受高氧暴露、残余油飞灰、流感肺炎、出血诱导的肺损伤、放射性肺炎、博来霉素诱导的肺纤维化的急性肺损伤,并在新生儿高氧模型中保护肺发育。在心血管疾病模型中,EC-SOD可防止缺血再灌注损伤,减轻高血压,并且特定的多态性可显著增加缺血性心脏病的风险。尽管这项工作,EC-SOD在这些疾病过程中的保护作用的确切机制仍不清楚。最近,我们已经开始解开重要的因素,在调节EC-SOD组织和细胞特异性表达。在这个竞争性的更新应用中,我们将建立在我们最近的发现基础上,这些发现已经开始探索控制EC-SOD基因表达的分子途径。基于我们对人类和小鼠EC-SOD基因的初步表征,我们现在假设EC-SOD的转录表达受转录因子家族(Ets、MZF-1、Kruppel和Sp1/Sp3)的调控,所述转录因子家族在位于小鼠EC-SOD基因5 '非翻译区的近端和远端启动子元件处相互作用。进一步提出,这些元件的活性受到包括组蛋白乙酰化和甲基化的表观遗传过程的调节。为了验证这些假设,我们提出了三个具体目标。目的1将研究顺式元件和反式激活因子调节基础和细胞特异性EC-SOD在肺中的表达的贡献和鉴定。在目标2中,我们将确定和表征负责EC-SOD基因转录调控的转录因子元件。目的3将使用一种新的体内生物发光成像系统,利用新发现的EC-SOD近端和远端启动子元件在转基因小鼠中检测功能和空间基因表达谱。预计这项工作将为我们理解EC-SOD基因表达调控的分子机制提供新的见解。这可能导致新的药理学策略,用于增加肺和其他组织中的内源性EC-SOD水平,这将被预测为减少细胞外氧化应激和减弱肺部疾病过程。

项目成果

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RODNEY J FOLZ其他文献

RODNEY J FOLZ的其他文献

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{{ truncateString('RODNEY J FOLZ', 18)}}的其他基金

Asthma in Older Adults: Identifying Phenotypes and Factors Impacting Outcomes
老年人哮喘:识别表型和影响结果的因素
  • 批准号:
    9222689
  • 财政年份:
    2015
  • 资助金额:
    $ 38.88万
  • 项目类别:
Asthma in Older Adults: Identifying Phenotypes and Factors Impacting Outcomes
老年人哮喘:识别表型和影响结果的因素
  • 批准号:
    8998910
  • 财政年份:
    2015
  • 资助金额:
    $ 38.88万
  • 项目类别:
Asthma in Older Adults: Identifying Phenotypes and Factors Impacting Outcomes
老年人哮喘:识别表型和影响结果的因素
  • 批准号:
    9419265
  • 财政年份:
    2015
  • 资助金额:
    $ 38.88万
  • 项目类别:
Mechanisms of lung injury following autologous BMT
自体骨髓移植后肺损伤的机制
  • 批准号:
    7092583
  • 财政年份:
    2003
  • 资助金额:
    $ 38.88万
  • 项目类别:
Mechanisms of lung injury following autologous BMT
自体骨髓移植后肺损伤的机制
  • 批准号:
    7514742
  • 财政年份:
    2003
  • 资助金额:
    $ 38.88万
  • 项目类别:
Mechanisms of lung injury following autologous BMT
自体骨髓移植后肺损伤的机制
  • 批准号:
    6920813
  • 财政年份:
    2003
  • 资助金额:
    $ 38.88万
  • 项目类别:
Mechanisms of lung injury following autologous BMT
自体骨髓移植后肺损伤的机制
  • 批准号:
    6783298
  • 财政年份:
    2003
  • 资助金额:
    $ 38.88万
  • 项目类别:
Mechanisms of lung injury following autologous BMT
自体骨髓移植后肺损伤的机制
  • 批准号:
    6676506
  • 财政年份:
    2003
  • 资助金额:
    $ 38.88万
  • 项目类别:
REGULATION AND FUNCTION OF EC-SOD
EC-SOD的调节和功能
  • 批准号:
    6527447
  • 财政年份:
    2000
  • 资助金额:
    $ 38.88万
  • 项目类别:
REGULATION AND FUNCTION OF EC-SOD
EC-SOD的调节和功能
  • 批准号:
    6654859
  • 财政年份:
    2000
  • 资助金额:
    $ 38.88万
  • 项目类别:

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  • 批准号:
    82370988
  • 批准年份:
    2023
  • 资助金额:
    48.00 万元
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靶向小儿胶质瘤的转录延伸
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  • 批准号:
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  • 财政年份:
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基于机制的组蛋白脱乙酰酶抑制剂与 PARP 抑制剂联合治疗 AML
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    2017
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用于活体动物组蛋白甲基化成像的分子传感器
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    9089934
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    2012
  • 资助金额:
    $ 38.88万
  • 项目类别:
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