Diabetic Vasculopathy and Mitochondrial eNOS

糖尿病血管病变和线粒体 eNOS

基本信息

  • 批准号:
    8613319
  • 负责人:
  • 金额:
    $ 41.41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-02-01 至 2017-01-31
  • 项目状态:
    已结题

项目摘要

Nitric oxide (NO) is produced by endothelial NO synthase (eNOS) and plays a key role in maintaining vascular health and renal function. Chronic exposure to high glucose triggers oxidation of tetrahydrobiopterin (BH4), an essential eNOS cofactor, resulting in accumulation of dihydrobiopterin (BH2) in the vascular endothelium. During the initial period of Merit Award support, we discovered that BH2 binds eNOS with high avidity, replacing BH4 and switching the eNOS product from NO to superoxide. Studies suggest that BH2 binding to eNOS can initiate a pivotal feed-forward molecular cascade that drives oxidative stress and NO insufficiency in diabetic blood vessels, responsible for severe diabetic vascular complications that can lead to amputations, blindness, kidney failure and death. Research also demonstrates the efficacy of a novel pharmacological approach for disrupting the cascade of NO insufficiency and oxidative stress in diabetic blood vessels, utilizing agents that release NO via efficient reaction with superoxide (and/or derived oxidants). Remarkably, superoxide-dependent NO release is a property of the eNOS catalytic intermediate, N'¿-hydroxyarginine (NOMA), an endogenous molecule that circulates in blood at 5-10 pM. By concurrently scavenging oxidants and releasing NO, administered NOMA can selectively target NO delivery to vascular sites of oxidative stress, increasing BH4:BH2 and restoring eNOS coupling and NO production. Indeed, chronic NOMA treatment of genetically-diabetic db/db prevented development of endothelial dysfunction, hypertension and NO insufficiency that othenwise occurred in vehicle-treated controls. NOMA (or a related hydroxyguanidine) could fill a major unmet clinical need, by providing targeted therapy for diabetic vasculapathies as a first-in-class superoxide-dependent NO-releasing agent. The overall goal of studies proposed during this Merit Award extension period is to enhance our biochemical understanding of the role of NO in diabetes and extend our assessment of NOHA for potential therapy of diabetic vasculopathies. This will include evaluation of NOHA pharmacokinetics, metabolism, reaction mechanisms, effects on metabolism and therapeutic benefit in rodent models of diabetes-impaired wound healing, angiogenesis and limb blood flow insufficiency. Studies will rely on new research approaches and assays, established during the initial Merit Award period - including a powerful LC/MS/MS platform for global untargeted metabolite profiling (to survey expression changes in thousands of molecules, 50 - 1000 m/z) and a proteomic approach for discovering nitrated proteins and sites that result from uncoupled eNOS and may contribute to vasculopathy.
一氧化氮(NO)是由内皮型一氧化氮合酶(eNOS)产生的,在维持血管健康和肾功能中起关键作用。长期暴露于高葡萄糖会触发四氢生物蝶呤(BH 4)(一种必需的eNOS辅因子)的氧化,导致二氢生物蝶呤(BH 2)在血管内皮中蓄积。在优异奖支持的最初阶段,我们发现BH 2以高亲和力结合eNOS,取代BH 4并将eNOS产物从NO转换为超氧化物。研究表明,BH 2与eNOS的结合可以启动一个关键的前馈分子级联反应,驱动糖尿病血管中的氧化应激和NO不足,导致严重的糖尿病血管并发症,可导致截肢、失明、肾衰竭和死亡。研究还证明了一种新的药理学方法用于破坏糖尿病血管中NO不足和氧化应激的级联的功效,该方法利用通过与超氧化物(和/或衍生的氧化剂)的有效反应释放NO的试剂。值得注意的是,超氧化物依赖性NO释放是eNOS催化中间体N '-羟基精氨酸(NOMA)的性质,N'-羟基精氨酸(NOMA)是一种以5-10 pM在血液中循环的内源性分子。通过同时清除氧化剂和释放NO,施用的NOMA可以选择性地将NO递送靶向氧化应激的血管部位,增加BH 4:BH 2并恢复eNOS偶联和NO产生。的确, 遗传性糖尿病db/db的长期NOMA治疗防止了内皮功能障碍、高血压和NO不足的发展,而这些在载体治疗的对照中则会发生。NOMA(或相关的羟基胍)可以通过作为一流的超氧化物依赖性NO释放剂为糖尿病血管病变提供靶向治疗来填补主要的未满足的临床需求。在此优异奖延长期内提出的研究的总体目标是提高我们对生物化学作用的理解。 的NO在糖尿病和扩展我们的评估NOHA的潜在治疗糖尿病血管病变。这将包括在糖尿病受损伤口愈合、血管生成和肢体血流不足的啮齿动物模型中评价NOHA药代动力学、代谢、反应机制、对代谢的影响和治疗获益。研究将依赖于新的研究方法和分析,建立在最初的 优异奖期间-包括用于全球非靶向代谢物分析的强大LC/MS/MS平台(以调查数千个分子的表达变化,50 - 1000 m/z)和用于发现硝化蛋白质和位点的蛋白质组学方法,这些蛋白质和位点由解偶联eNOS产生,可能导致血管病变。

项目成果

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Steven S Gross其他文献

Steven S Gross的其他文献

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{{ truncateString('Steven S Gross', 18)}}的其他基金

Predoctoral Training in Pharmacological Sciences
药理学博士前培训
  • 批准号:
    10617358
  • 财政年份:
    2021
  • 资助金额:
    $ 41.41万
  • 项目类别:
Predoctoral Training in Pharmacological Sciences
药理学博士前培训
  • 批准号:
    10414047
  • 财政年份:
    2021
  • 资助金额:
    $ 41.41万
  • 项目类别:
Predoctoral Training in Pharmacological Sciences
药理学博士前培训
  • 批准号:
    10206434
  • 财政年份:
    2021
  • 资助金额:
    $ 41.41万
  • 项目类别:
Purchase of a Triple Quadrupole Mass Spectrometry System for Metabolite Analysis
购买三重四极杆质谱系统用于代谢物分析
  • 批准号:
    7795361
  • 财政年份:
    2010
  • 资助金额:
    $ 41.41万
  • 项目类别:
Predoctoral Training in Pharmacological Sciences
药理学博士前培训
  • 批准号:
    7892142
  • 财政年份:
    2009
  • 资助金额:
    $ 41.41万
  • 项目类别:
Diabetic Vasculopathy and Mitochondrial eNOS
糖尿病血管病变和线粒体 eNOS
  • 批准号:
    8018678
  • 财政年份:
    2007
  • 资助金额:
    $ 41.41万
  • 项目类别:
Diabetic Vasculopathy and Mitochondrial eNOS
糖尿病血管病变和线粒体 eNOS
  • 批准号:
    7350221
  • 财政年份:
    2007
  • 资助金额:
    $ 41.41万
  • 项目类别:
Diabetic Vasculopathy and Mitochondrial eNOS
糖尿病血管病变和线粒体 eNOS
  • 批准号:
    7186905
  • 财政年份:
    2007
  • 资助金额:
    $ 41.41万
  • 项目类别:
Diabetic Vasculopathy and Mitochondrial eNOS
糖尿病血管病变和线粒体 eNOS
  • 批准号:
    8442791
  • 财政年份:
    2007
  • 资助金额:
    $ 41.41万
  • 项目类别:
Diabetic Vasculopathy and Mitochondrial eNOS
糖尿病血管病变和线粒体 eNOS
  • 批准号:
    8188798
  • 财政年份:
    2007
  • 资助金额:
    $ 41.41万
  • 项目类别:
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