INDUCIBLE NO SYNTHASE IN CARDIAC ALLOGRAFT REJECTION

心脏同种异体移植排斥反应中可诱导无合酶

• 批准号: 2702290
• 负责人: Paul J Cannon
• 金额: $ 29.27万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2702290
• 关键词: aminoacid transport; apoptosis; arginine; enzyme induction /repression; enzyme inhibitors; enzyme mechanism; heart transplantation; homologous transplantation; inflammation; laboratory mouse; muscle cells; myocardium; nitric oxide synthase; prostaglandin endoperoxide synthase; transplant rejection; transport inhibitor

DESCRIPTION: (Adapted from the applicant's abstract) The role of inducible nitric oxide synthase (iNOS) in the biochemistry and pathobiology of cardiac allograft rejection will be investigated. Previous work demonstrated that iNOS mRNA and enzyme activity was induced in macrophages infiltrating the myocardium and in cardiac myocytes during cardiac allograft rejection. The major hypothesis to be tested in this proposal is that NO in the rejecting graft augments myocardial inflammation and contributes to death of cardiac myocytes. These studies will address the following specific aims: 1) whether relatively selective iNOS inhibition will reduce myocardial inflammation and myocyte death in allografts, 2) whether inflammation and monocyte death is ameliorated by transplanting normal mouse hearts into mice genetically unable to induce iNOS (IRF-1 null mice), 3) if induction of cyclooxygenase-2 augments myocardial inflammation and myocyte necrosis, and if cyclooxygenase and iNOS inhibition ameliorate rejection. In addition, 4) a new strategy employing an arginine transport inhibitor which decreases NO synthesis will be examined for its effect on allograft rejection. Finally, 5) the mechanism by which NO produces death of cardiac myocytes will be investigated in detail. The results of the proposed experiments may provide new information concerning the role of iNOS in the pathobiology of cardiac rejection and suggest new therapies.

描述：（改编自申请人的摘要） 诱导型一氧化氮合酶（iNOS）在生物化学和 将研究心脏同种异体移植排斥的病理生物学。 以前的工作表明，诱导型一氧化氮合酶的mRNA和酶活性， 在浸润心肌的巨噬细胞和心脏中诱导 心脏移植排斥反应中的心肌细胞。 主要的假设是 在这个提议中被测试的是，在排斥移植物中的NO增加了 心肌炎症并导致心肌细胞死亡。 这些研究将针对以下具体目标：1） 相对选择性的iNOS抑制将减少心肌炎症 移植物中是否存在炎症和单核细胞 通过将正常小鼠心脏移植到小鼠体内， 遗传上不能诱导iNOS（IRF-1缺失小鼠），3）如果诱导 环氧合酶-2增强心肌炎症和肌细胞坏死， 以及环氧化酶和iNOS抑制是否改善排斥反应。 在 此外，4）采用精氨酸转运抑制剂的新策略 这将减少NO合成的影响， 同种异体移植排斥反应。 最后，5）NO产生的机制 将详细研究心肌细胞的死亡。 结果 建议的实验可能会提供新的信息， iNOS在心脏排斥反应病理学中的作用，并提示新的 治疗