Oxidative Stress and Vascular HO in Diabetes
糖尿病中的氧化应激和血管 H2O2
基本信息
- 批准号:7630645
- 负责人:
- 金额:$ 5.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-08-15 至 2011-07-31
- 项目状态:已结题
- 来源:
- 关键词:Adenovirus VectorAnimalsApoptosisApoptoticAttenuatedBilirubinBiliverdineBlood VesselsCarbon MonoxideCardiovascular DiseasesCardiovascular systemCell Adhesion MoleculesCell DeathCellsComplicationCytoplasmCytoprotectionDepthDevelopmentDiabetes MellitusDiabetic AngiopathiesDiabetic mouseElevated BilirubinEndothelial CellsExperimental Diabetes MellitusFree RadicalsFunctional disorderGene ExpressionGene TargetingGene TransferGenesGeneticGerm LinesGoalsHemeHumanHyperglycemiaIn VitroInbred NOD MiceInflammationInjuryInsulinInsulin-Dependent Diabetes MellitusIsoenzymesLaboratoriesLeadLentivirus VectorMediatingMitochondriaMorbidity - disease rateMusOxidative StressOxygenasesPathway interactionsPatientsPharmaceutical PreparationsPhysiologicalProtein OverexpressionProteinsPublishingRattusRelative (related person)Research ProposalsResistanceRetroviral VectorRoleSystemTestingTimeTransgenic MiceUp-RegulationVascular DiseasesVascular EndotheliumWorkbasecase controlcaspase-9cobaltiprotoporphyrincytochrome cdiabeticdiabetic ratgain of functiongene therapyheme oxygenase-1heme oxygenase-2improvedin vivoinnovationloss of functionmortalitymouse modelnovelpreventpromoterresponsestemtype I and type II diabetestype I diabeticvascular endothelial dysfunction
项目摘要
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, increase 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-1prevents endothelial apoptosis by decreasing cellular heme content, increasing CO and
bilirubin levels and decreasing EC-SOD and DMAdegradation. 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 Oa"and improved vascular
response. In addition, and 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-1and 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) 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
pverexpress 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.
大血管和微血管疾病是糖尿病患者发病和死亡的主要原因
项目成果
期刊论文数量(0)
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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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。
- DOI:
- 发表时间:
1991 - 期刊:
- 影响因子:11.1
- 作者:
R. Levere;Yi;A. Kappas;Doris Bucher;Gary P. Wormser;Nader G. Abraham - 通讯作者:
Nader G. Abraham
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:
$ 5.6万 - 项目类别:
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