Oxidative Stress and Vascular HO in Diabetes

糖尿病中的氧化应激和血管 H2O2

基本信息

项目摘要

DESCRIPTION (provided by applicant): Macro and microvascular diseases are the principal causes of morbidity and mortality in patients with type 1 and type 2 diabetes. Endothelial dysfunction, as evidenced by the increased release of free radicals, increases adhesion molecules and apoptosis. Previous work by us and others has shown that a decrease in HO-1 gene expression enhances apoptosis and vascular injury which can be prevented by pharmacological mediated upregulation of HO-1. Our preliminary results indicate that upregulation of HO-1 prevents endothelial apoptosis by decreasing cellular heme content, increasing CO and bilirubin levels and decreasing EC-SOD and DNA degradation. The goal of this proposal is to elucidate the mechanism by which HO-1 prevents diabetes-mediated endothelial dysfunction and to explore the use of genetic and/or pharmacological approaches to achieve long-term vascular protection. Our hypothesis is that HO-1 gene transfer will provide powerful vascular protection by increasing heme degradation and subsequently increasing CO and bilirubin synthesis. The increased levels of CO and bilirubin will result in an increase in EC-SOD, and eNOS, a decrease in O2- and improved vascular response. In addition, increase in mitochondrial HO-1 levels will increase mitochondrial transport carrier, decrease mitochondrial ROS and prevent release of cytochrome c and activation of caspase 9. We plan to test this hypothesis using genetic probes (retroviral LXSN lentiviral, and adenoviral) and in genetically spontaneously diabetic mice, (NOD) mice. We will use the loss-of-function HO-2 (-/-) and gain-of-function, HO-1 and HO-2 gene transfer to HO-2 (-/-) to decipher the role of each gene in vascular protection. The following specific aims will test the hypothesis. (1)To determine whether genetic intervention, using retroviral vectors, to selectively increases HO-1 provides vascular protection in diabetic rats and NOD mice, and whether this effect is due to CO, bilirubin or both. We will examine the effect HO-1 derived CO and bilirubin on EC-SOD, eNOS and O2- levels. (2) HO-2 (-/-) and NOD mice will be used to test the hypothesis that HO-1 gene transfer can provide vascular protection and that CO, bilirubin or both are obligatory for the vascular protection via increase in EC-SOD, eNOS, decrease in O2- and iNOS. (3)To determine the mechanism whereby HO-1 gene expression (CO and bilirubin) act on the extrinsic and intrinsic pathway of pro-apoptosis and anti-apoptotic proteins. This will examine the role of CO and bilirubin produced by HO-1 in both the mitochondria and cytoplasm. (4) To evaluate whether lentiviral vectors targeting endothelial cells using cell specific promoter (VE-CAD) to overexpress HO-1 gene is sufficient to offset diabetes-induced vascular injury. This proposal is novel in its approach. It will allow for the first time, an in-depth analysis of the function of HO-1 in vascular protection and for the development of innovative gene-targeting therapies for the treatment of type I diabetes.
描述(申请人提供):大血管和微血管疾病是1型和2型糖尿病患者发病和死亡的主要原因。内皮功能障碍,如自由基释放增加所证明的,增加黏附分子和细胞凋亡。我们和其他人以前的工作表明,HO-1基因表达的减少会促进细胞凋亡和血管损伤,这可以通过药物介导的HO-1上调来防止。我们的初步结果表明,HO-1的上调通过减少细胞中的血红素含量,增加CO和胆红素水平,减少EC-SOD和DNA的降解来防止内皮细胞的凋亡。该提案的目的是阐明HO-1预防糖尿病介导的内皮功能障碍的机制,并探索使用遗传和/或药物方法来实现长期的血管保护。我们的假设是,HO-1基因转移将通过增加血红素的降解从而增加一氧化碳和胆红素的合成来提供强大的血管保护。CO和胆红素水平的升高将导致EC-SOD和eNOS的升高,O2-的降低和血管反应的改善。此外,线粒体HO-1水平的增加将增加线粒体运输载体,降低线粒体ROS,阻止细胞色素c的释放和caspase 9的激活。我们计划使用遗传探针(逆转录病毒LXSN慢病毒和腺病毒)和遗传性自发性糖尿病小鼠(NOD)来验证这一假说。我们将利用功能丧失的HO-2(-/-)和功能获得的HO-1和HO-2基因转移到HO-2(-/-)来破译每个基因在血管保护中的作用。以下具体目标将检验这一假设。(1)确定利用逆转录病毒载体选择性增加HO-1的基因干预是否对糖尿病大鼠和NOD小鼠提供血管保护,以及这种影响是由于一氧化碳、胆红素还是两者兼而有之。我们将检测HO-1衍生的CO和胆红素对EC-SOD、eNOS和O2-水平的影响。(2)HO-2(-/-)和NOD小鼠将被用来验证HO-1基因转移可以提供血管保护的假设,以及CO、胆红素或两者都是通过增加EC-SOD、eNOS、减少O2-和iNOS来实现血管保护的假说。(3)探讨HO-1基因表达(CO和胆红素)在促凋亡和抗凋亡蛋白的外在和内在途径中的作用机制。这将检验HO-1在线粒体和细胞质中产生的一氧化碳和胆红素的作用。(4)评价以细胞特异性启动子(VE-CAD)为靶点的慢病毒载体过表达HO-1基因是否足以抵消糖尿病血管损伤。这项建议在方法上是新颖的。这将首次深入分析HO-1在血管保护中的功能,并为治疗I型糖尿病开发创新的基因靶向疗法。

项目成果

期刊论文数量(0)
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Nader G. Abraham其他文献

Significance of heme oxygenase in cardiovascular diseases
  • DOI:
    10.1016/j.biopha.2008.07.038
  • 发表时间:
    2008-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    Nader G. Abraham
  • 通讯作者:
    Nader G. Abraham
RETRACTED ARTICLE: The Na/K-ATPase Oxidant Amplification Loop Regulates Aging
撤回文章:钠钾-ATP 酶氧化剂放大环调节衰老
  • DOI:
    10.1038/s41598-018-26768-9
  • 发表时间:
    2018-06-26
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Komal Sodhi;Alexandra Nichols;Amrita Mallick;Rebecca L. Klug;Jiang Liu;Xiaoliang Wang;Krithika Srikanthan;Perrine Goguet-Rubio;Athar Nawab;Rebecca Pratt;Megan N. Lilly;Juan R. Sanabria;Zijian Xie;Nader G. Abraham;Joseph I. Shapiro
  • 通讯作者:
    Joseph I. Shapiro
Heme inhibits human immunodeficiency virus 1 replication in cell cultures and enhances the antiviral effect of zidovudine.
血红素可抑制人类免疫缺陷病毒 1 在细胞培养物中的复制,并增强齐多夫定的抗病毒作用。
Mechanisms of Physical and Emotional Stress
身体和情绪压力的机制
  • DOI:
    10.1007/978-1-4899-2064-5
  • 发表时间:
    1988
  • 期刊:
  • 影响因子:
    0.9
  • 作者:
    Irun R. Cohen;Mehdi Tavassoli;E. Zanjani;Joao L. Ascensao;Nader G. Abraham;Lynn Loriaux;G. Chrousos;P. Gold
  • 通讯作者:
    P. Gold
HO-1 pharmacological over-expression in a rat model of Type II diabetes: implications for microvascular tone and the genesis of ischemia
  • DOI:
    10.1016/j.biopha.2008.07.044
  • 发表时间:
    2008-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    Cecilia Vecoli;Danilo Neglia;Daniela Giannessi;Maristella Maltinti;Michela Novelli;Pellegrino Masiello;Nader G. Abraham;Nazareno Paolocci;L'Abbate Antonio
  • 通讯作者:
    L'Abbate Antonio

Nader G. Abraham的其他文献

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{{ truncateString('Nader G. Abraham', 18)}}的其他基金

Adipocyte EET-PGC1alpha-HO-1 in Obesity-driven Hypertension
肥胖引起的高血压中的脂肪细胞 EET-PGC1α-HO-1
  • 批准号:
    9769285
  • 财政年份:
    2018
  • 资助金额:
    $ 24.18万
  • 项目类别:
Oxidative Stress and Vascular HO in Diabetes
糖尿病中的氧化应激和血管 H2O2
  • 批准号:
    8031600
  • 财政年份:
    2010
  • 资助金额:
    $ 24.18万
  • 项目类别:
Oxidative Stress and Vascular HO in Diabetes
糖尿病中的氧化应激和血管 H2O2
  • 批准号:
    7145623
  • 财政年份:
    2006
  • 资助金额:
    $ 24.18万
  • 项目类别:
Oxidative Stress and Vascular HO in Diabetes
糖尿病中的氧化应激和血管 H2O2
  • 批准号:
    7630645
  • 财政年份:
    2006
  • 资助金额:
    $ 24.18万
  • 项目类别:
Oxidative Stress and Vascular HO in Diabetes
糖尿病中的氧化应激和血管 H2O2
  • 批准号:
    7893856
  • 财政年份:
    2006
  • 资助金额:
    $ 24.18万
  • 项目类别:
Oxidative Stress and Vascular HO in Diabetes
糖尿病中的氧化应激和血管 H2O2
  • 批准号:
    7440201
  • 财政年份:
    2006
  • 资助金额:
    $ 24.18万
  • 项目类别:
Oxidative Stress and Vascular HO in Diabetes
糖尿病中的氧化应激和血管 H2O2
  • 批准号:
    7276681
  • 财政年份:
    2006
  • 资助金额:
    $ 24.18万
  • 项目类别:
Oxidative Stress and Vascular HO in Diabetes
糖尿病中的氧化应激和血管 H2O2
  • 批准号:
    7632248
  • 财政年份:
    2006
  • 资助金额:
    $ 24.18万
  • 项目类别:
CORE--GENE TRANSFER
核心——基因转移
  • 批准号:
    6796317
  • 财政年份:
    2003
  • 资助金额:
    $ 24.18万
  • 项目类别:
CORE--GENE TRANSFER
核心——基因转移
  • 批准号:
    6653346
  • 财政年份:
    2002
  • 资助金额:
    $ 24.18万
  • 项目类别:

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