MOLECULAR TARGETS OF NITRIC OXIDE IN CARDIAC TRANSPLANTS

心脏移植中一氧化氮的分子靶标

基本信息

  • 批准号:
    6537767
  • 负责人:
  • 金额:
    $ 37.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2001
  • 资助国家:
    美国
  • 起止时间:
    2001-07-01 至 2005-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (Verbatim from the application): While nitric oxide (NO) is believed to contribute to cardiac allograft rejection, me precise mechanism is not understood. We will examine the intracellular molecular mechanisms for the actions of excess NO on cardiac allograft contractile dyskinesis relating to a paradigm which includes both oxidative and nitrosative stress. We will examine the regulation of inducible NO synthase (iNOS) gene expression by the oxidant-sensitive NF-kB transcription factor and examine key candidate cytosolic and mitochondrial proteins as molecular targets of NO. These proteins include myoglobin and aconitase. In vitro nitrosylation of these proteins are known to inhibit enzyme activity and 02 binding, thus, interfering with efficient 02 utilization by this O2-demanding organ. Hypothesis: [NO derived from iNOS targets certain cellular proteins for nitrosylation within cardiac grafts that contribute to myocardial contractile dysfunction. Furthermore, reactive oxygen plays a role in regulating iNOS gene expression at the transcriptional level via activation of the oxidant-sensitive transcription factor (NF-KB).] The applicant will use advanced, state-of-the-art molecular and biophysical techniques including: transcription factor regulation of iNOS gene (gel shift assays; Northern and Western analysis); in situ sonomicrometry; measures of nitrosyl protein and function (EPR, electron paramagnetic resonance spectroscopy and immunoprecipitation); assay for apoptosis; quantitation of reactive oxygen (EPR spin trapping; salicylate trapping); evaluation with iNOS knockout and SOD1 or SOD2 transgenic mice. The applicant will show that following allogeneic cardiac transplantation: Aim #1: [Induction of iNOS leads to iron-nitrosyl complex formation within myocardium and contractile dysfunction during allogeneic cardiac transplantation.]; Aim #2: [Certain candidate proteins are molecular targets of nitrosylation by excess NO in allogeneic transplantation.]; Aim #3: [iNOS gene deletion prevents nitrosyiprotein formation and prolongs graft survival. ]; Aim #4: [iNOS gene expression during allogeneic transplantation is regulated by activation of NF-KB.]; Aim #5: [Antioxidants inhibit activation of NF-KB, induction of iNOS, formation of nitrosyl complexes and enhance contractile function.]; Aim #6: [Antioxidant transgene overexpression inhibits activation of NF-kB, induction of iNOS, formation of nitrosyl complexes and enhances contractile function during allogeneic cardiac transplantion.] These studies will provide a novel mechanism to explain the pathogenesis of dyskinesis and graft failure during cardiac transplant rejection.
说明(原文来自申请书):当一氧化氮(NO)是

项目成果

期刊论文数量(0)
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GALEN M PIEPER其他文献

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{{ truncateString('GALEN M PIEPER', 18)}}的其他基金

iNOS Posttranslational Regulation in Cardiac Rejection
心脏排斥反应中 iNOS 的翻译后调节
  • 批准号:
    7373617
  • 财政年份:
    2006
  • 资助金额:
    $ 37.5万
  • 项目类别:
iNOS Posttranslational Regulation in Cardiac Rejection
心脏排斥反应中 iNOS 的翻译后调节
  • 批准号:
    7195832
  • 财政年份:
    2006
  • 资助金额:
    $ 37.5万
  • 项目类别:
iNOS Posttranslational Regulation in Cardiac Rejection
心脏排斥反应中 iNOS 的翻译后调节
  • 批准号:
    7579150
  • 财政年份:
    2006
  • 资助金额:
    $ 37.5万
  • 项目类别:
iNOS Posttranslational Regulation in Cardiac Rejection
心脏排斥反应中 iNOS 的翻译后调节
  • 批准号:
    7088167
  • 财政年份:
    2006
  • 资助金额:
    $ 37.5万
  • 项目类别:
MOLECULAR TARGETS OF NITRIC OXIDE IN CARDIAC TRANSPLANTS
心脏移植中一氧化氮的分子靶标
  • 批准号:
    6638613
  • 财政年份:
    2001
  • 资助金额:
    $ 37.5万
  • 项目类别:
MOLECULAR TARGETS OF NITRIC OXIDE IN CARDIAC TRANSPLANTS
心脏移植中一氧化氮的分子靶标
  • 批准号:
    6755178
  • 财政年份:
    2001
  • 资助金额:
    $ 37.5万
  • 项目类别:
MOLECULAR TARGETS OF NITRIC OXIDE IN CARDIAC TRANSPLANTS
心脏移植中一氧化氮的分子靶标
  • 批准号:
    6258634
  • 财政年份:
    2001
  • 资助金额:
    $ 37.5万
  • 项目类别:
PARAMAGNETIC COMPLEXES IN ALLOGENIC HETEROTROPIC CARDIAC TRANSPLANTS
同种异体异向性心脏移植中的顺磁性复合物
  • 批准号:
    6118848
  • 财政年份:
    1999
  • 资助金额:
    $ 37.5万
  • 项目类别:
DIABETES, TRANSPLANTATION AND VASCULAR ENDOTHELIUM
糖尿病、移植和血管内皮
  • 批准号:
    2223385
  • 财政年份:
    1993
  • 资助金额:
    $ 37.5万
  • 项目类别:
DIABETES, TRANSPLANTATION AND VASCULAR ENDOTHELIUM
糖尿病、移植和血管内皮
  • 批准号:
    2223386
  • 财政年份:
    1993
  • 资助金额:
    $ 37.5万
  • 项目类别:

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