Mechanisms of Redox Mediated Cardioprotection

描述：(申请人提供)本研究的目标是确定 导致癌症治疗期间心脏保护的新机制。在……里面 心脏组织，细胞毒性和细胞保护作用都涉及到 肿瘤坏死因子α的作用。虽然各种癌症 治疗药物已被证明可诱导肿瘤坏死因子α和 这两种类型的肿瘤坏死因子受体(p55和p75)都在心肌细胞中表达， 这一细胞因子及其相关受体在心脏应激反应中的作用 癌症的治疗方法是未知的。抗雌激素的三苯氧胺()已被证明 不仅有益于缩小对侧乳房 癌症还能降低癌症中心脏病的发病率 病人。他莫昔芬通常被认为是乳房中的一种抗雌激素 癌症抑制肿瘤生长。然而，观察到的心脏保护作用 在不同的临床试验中表明其作用机制 抗雌激素是复杂的，不能简单地描述为缺乏雌激素。 肿瘤坏死因子受体对ADR所致心脏损伤更敏感 对肿瘤坏死因子p75的抑制作用呈剂量依赖性 受体与肿瘤坏死因子α诱导的线粒体损伤的抑制。这些 结果表明，低水平的内源性肿瘤坏死因子可能具有心脏保护作用。 而高水平的肿瘤坏死因子α对心脏有毒性。我们假设1) 内源性肿瘤坏死因子α通过快速激活 阻止。我们的初步数据表明，缺乏核因子的突变小鼠 Kappa Beta(NFkBeta)，随后诱导保护蛋白；2)高 肿瘤坏死因子α水平导致过量的肿瘤坏死因子受体介导的诱导 线粒体损伤；3)线粒体抗氧化能力增强 改善诱导的心脏保护作用。肿瘤坏死因子α和在心脏疾病中的作用 将在动物身上建立损伤，分离线粒体，并分离 心肌细胞。转基因动物将被用来研究 肿瘤坏死因子/与线粒体抗氧化状态在心脏保护中的联系。 拟议的研究将提供有关该角色的基本信息 肿瘤坏死因子和在心脏损伤中的作用。这一结果还应该为我们提供关于 线粒体抗氧化状态与的关系。结果可能是 导致制定有选择的办法，以改善对 心脏，从而降低自由基相关抗癌的毒性 探员们。

DESCRIPTION: (provided by applicant) The goal of this study is to identify novel mechanisms leading to cardioprotection during cancer treatment. In cardiac tissue, both cytotoxic and cytoprotective actions are implicated in the action of tumor necrosis factor alpha (TNFalpha). Although a variety of cancer therapeutic agents have been shown to induce rapid expression of TNFalpha and both types of TNF receptors (p55 and p75) are expressed in cardiomyocytes, the role of this cytokine and its associated receptors in cardiac response to cancer therapy is unknown. The anti-estrogen tamoxifen (TAM) has been shown to have a beneficial effect not only in the reduction of contralateral breast cancer but also to result in a reduced incidence of heart disease in cancer patients. Tamoxifen is generally thought to act as an anti-estrogen in breast cancer to inhibit tumor growth. However, the cardioprotective effect observed in various clinical trials suggests that the mechanism of action of anti-estrogens is complex and cannot be described simply as an estrogen lacking TNF receptors are more sensitive to ADR-induced cardiac injury and that pre-treatment with TAM results in a dose-dependent reduction of the p75 TNF receptor and suppression of TNFalpha-induced mitochondrial injury. These results suggest that low levels of endogenous TNF may be cardioprotective whereas high levels of TNFalpha are cardiotoxic. We hypothesized that 1) endogenous TNFalpha serves a cardioprotective role by rapid activation of the block. Our preliminary data indicate that mutant mice lacking nuclear factor kappa Beta (NFkBeta) with subsequent induction of protective proteins; 2) high levels of TNFalpha cause excessive TNF-receptors mediated-induction of mitochondrial injury; and 3) enhancement of mitochondrial antioxidant capacity improves TAM-induced cardioprotection. The role of TNFalpha and TAM in cardiac injury will be established in animals, isolated mitochondria, and isolated cardiomyocytes. Genetically modified animals will be used to investigate the link between TNF/TAM and mitochondrial antioxidant status in cardioprotection. The proposed studies will provide fundamental information concerning the role of TNF and TAM in cardiac injury. The results should also provide insights into the link between mitochondrial antioxidant status and TAM. The results could lead to the development of selective approaches to improve protection of the heart, thus reducing the toxicity of free radical-associated anti-cancer agents.