Peroxisome Proliferator-Activated Receptor and Stroke

过氧化物酶体增殖物激活受体和中风

基本信息

  • 批准号:
    8448194
  • 负责人:
  • 金额:
    $ 27.49万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2005
  • 资助国家:
    美国
  • 起止时间:
    2005-09-15 至 2015-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant Stroke is the third leading cause of death and the primary cause of functional disability in the United States. This competitive R01 renewal application requests five years of support to discover a novel therapeutic target against ischemic stroke. Fibrates are peroxisome proliferator-activated receptor alpha (PPARa) agonists and have been prescribed as lipid normalizing drugs. Recent experimental evidence suggests that fibrates are beneficial against neurological diseases including ischemic stroke. In the previous funding cycle, we showed that two fibrates, fenofibrate and gemfibrozil, significantly improved cerebral blood flow after focal ischemia and reduced subsequent infarct size in mice. Fibrates strongly inhibited brain inflammation. The efficacies were independent of their lipid lowering effects but required PPARa expression. Based on these findings, we will further elucidate the downstream linking of PPARa activation to the cerebrovascular efficacies. We are focusing on copper chaperone proteins and superoxide dismutase (SOD) as the mediators of the cerebrovascular efficacies. Both cytosolic isoform (SOD1) and extracellular isoform (SOD3) require copper for their full activity. Our preliminary study showed that fenofibrate and gemfibrozil strongly elevated SOD3 activity levels in the brain. In addition, fenofibrate and gemfibrozil elevated copper chaperone for SOD3, Atox1 mRNA level. These elevations were not seen in PPARa null mice. We hypothesize that Atox1 elevation by PPARa activation pronounces SOD3 activity, which contributes to the cerebrovascular protection by fibrates. We will conduct comprehensive experiments using a well characterized mouse stroke model in several different mutant strains. Aim 1 is to demonstrate SOD3 as a mediator of cerebrovascular protection by fenofibrate. Aim 2 is to demonstrate that Atox1 contributes to the SOD3 elevation and subsequent cerebrovascular protection by fibrates. Aim 3 is to test whether or not peripheral blood cells are additional action sites for the PPARa -> Atox1 -> SOD3 axis activation to lead to the cerebrovascular protection. The proposed study will provide the first evidence that Atox1 may be a potential therapeutic target against ischemic stroke. Obtained knowledge will increase our understanding about the importance of copper trafficking in cerebrovascular diseases.
描述(由申请人提供)在美国,中风是第三大死亡原因,也是功能性残疾的主要原因。这项竞争性的R 01更新申请要求五年的支持,以发现一种新的治疗缺血性卒中的靶点。贝特类是过氧化物酶体增殖物激活受体α(PPARa)激动剂,已被处方为脂质正常化药物。最近的实验证据表明,贝特类药物对神经系统疾病,包括缺血性中风有益。在之前的资助周期中,我们发现两种贝特类药物,非诺贝特和吉非贝齐,显著改善了小鼠局灶性缺血后的脑血流量,并减少了随后的梗死面积。贝特类药物强烈抑制脑部炎症。功效不依赖于它们的降脂作用,但需要PPARa表达。基于这些发现,我们将进一步阐明PPARa活化与脑血管功效的下游联系。我们专注于铜伴侣蛋白和超氧化物歧化酶(SOD)作为脑血管疗效的介质。细胞溶质同种型(SOD 1)和细胞外同种型(SOD 3)都需要铜才能发挥全部活性。我们的初步研究表明,非诺贝特和吉非贝齐强烈提高SOD 3活性水平在大脑中。此外,非诺贝特和吉非贝齐提高铜伴侣SOD 3,Atox 1 mRNA水平。在PPARa缺失小鼠中未观察到这些升高。我们推测,Atox 1升高PPARa激活宣布SOD 3活性,这有助于脑血管保护贝特类。我们将在几种不同的突变品系中使用充分表征的小鼠中风模型进行综合实验。目的1是证明SOD 3作为非诺贝特脑血管保护的介质。目的2是证明Atox 1有助于贝特类药物升高SOD 3和随后的脑血管保护。目的3:检测外周血细胞是否为PPARa -> Atox 1-> SOD 3轴激活的额外作用位点,从而导致脑血管保护。这项研究将首次证明Atox 1可能是缺血性卒中的潜在治疗靶点。获得的知识将增加我们对铜转运在脑血管疾病中的重要性的理解。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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SHOBU NAMURA其他文献

SHOBU NAMURA的其他文献

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{{ truncateString('SHOBU NAMURA', 18)}}的其他基金

Gammacell 1000 Elite Self-Contained Blood Irradiator
Gammacell 1000 Elite 独立式血液辐照器
  • 批准号:
    8442779
  • 财政年份:
    2013
  • 资助金额:
    $ 27.49万
  • 项目类别:
Peroxisome Proliferator-Activated Receptor and Stroke
过氧化物酶体增殖物激活受体和中风
  • 批准号:
    7276057
  • 财政年份:
    2005
  • 资助金额:
    $ 27.49万
  • 项目类别:
Peroxisome Proliferator-Activated Receptor and Stroke
过氧化物酶体增殖物激活受体和中风
  • 批准号:
    8293098
  • 财政年份:
    2005
  • 资助金额:
    $ 27.49万
  • 项目类别:
Peroxisome Proliferator-Activated Receptor and Stroke
过氧化物酶体增殖物激活受体和中风
  • 批准号:
    7122507
  • 财政年份:
    2005
  • 资助金额:
    $ 27.49万
  • 项目类别:
Peroxisome Proliferator-Activated Receptor and Stroke
过氧化物酶体增殖物激活受体和中风
  • 批准号:
    7244926
  • 财政年份:
    2005
  • 资助金额:
    $ 27.49万
  • 项目类别:
Peroxisome Proliferator-Activated Receptor and Stroke
过氧化物酶体增殖物激活受体和中风
  • 批准号:
    8107288
  • 财政年份:
    2005
  • 资助金额:
    $ 27.49万
  • 项目类别:
Peroxisome Proliferator-Activated Receptor and Stroke
过氧化物酶体增殖物激活受体和中风
  • 批准号:
    7454241
  • 财政年份:
    2005
  • 资助金额:
    $ 27.49万
  • 项目类别:
Peroxisome Proliferator-Activated Receptor and Stroke
过氧化物酶体增殖物激活受体和中风
  • 批准号:
    7635762
  • 财政年份:
    2005
  • 资助金额:
    $ 27.49万
  • 项目类别:
Peroxisome Proliferator-Activated Receptor and Stroke
过氧化物酶体增殖物激活受体和中风
  • 批准号:
    6969507
  • 财政年份:
    2005
  • 资助金额:
    $ 27.49万
  • 项目类别:
Combination theraphy of betaine and fenofibrate against delayed neuronal
甜菜碱与非诺贝特联合治疗迟发性神经元
  • 批准号:
    8719199
  • 财政年份:
  • 资助金额:
    $ 27.49万
  • 项目类别:

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