Signal Transduction in the Heart after Cancer Therapy

描述（由申请人提供）：靶向癌症治疗的新方法已经得到了很好的接受，但一个潜在的主题需要解决。许多针对癌症治疗的蛋白质在心脏中也起着重要作用。我们实验室的长期目标是更好地了解erbB2和HSP90在心脏中的功能，识别有癌症治疗心脏损伤风险的患者，并制定新的治疗策略，既能有效治疗癌症，又能保护心脏免受癌症治疗药物的伤害。我们假设erbB2在心脏中是由氧化应激诱导的，并且它在保护心脏免受氧化应激（包括阿霉素治疗引起的应激）方面也起着核心作用。此外，我们假设伴侣蛋白HSP90通过稳定心脏细胞中的erbB2蛋白而参与这种细胞保护。目的1：通过以下氧化应激模型，确定氧化应激和相关细胞信号通过erbB2或HSP90（蛋白或mRNA）诱导心脏保护的作用以及NF-:2的作用：1)大鼠心肌细胞中H2O2、黄嘌呤/黄嘌呤氧化酶和谷胱甘肽耗竭和谷胱甘肽耗竭；2)糖尿病心肌病；3)白藜芦醇或香叶酮氧化还原调节以预防阿霉素毒性。此外，我们将确定自由基清除剂对erbB2表达的作用，以及erbB2途径抑制在氧化应激过程中对细胞保护的作用。目的2：确定erbB2的心脏保护作用是否由于心脏氧化应激的减少。我们的目标是评估：1)心肌细胞erbB2通路抑制（通过抗erbB2或siRNA）导致线粒体氧化应激和功能障碍增加，从而增加对阿霉素的敏感性；2)与癌症异种移植相比，拉帕替尼在体内诱导心脏氧化应激和细胞死亡，无论是否使用阿霉素治疗。3)转基因erbB2在两种氧化应激模型（阿霉素诱导的心肌病和链脲霉素诱导的糖尿病心肌病）中保护氧化应激和线粒体功能障碍。目的3：确定HSP90作为erbB2蛋白伴侣在心脏中的细胞保护作用。本研究旨在评估：1)在阿霉素诱导的心脏毒性或链脲霉素诱导的糖尿病心肌病两种模型中，转基因小鼠模型中心脏特异性过表达HSP90是否通过稳定erbB2来减少心衰、细胞死亡和氧化应激；2)体外用siRNA或体内用17AAG抑制HSP90蛋白表达或功能会增加阿霉素治疗期间的心肌细胞死亡。3)HSP90抑制剂（17AAG）影响离体心脏erbB2水平，抑制心功能和线粒体功能。公共卫生相关性：该项目的公共卫生意义在于，我们旨在保护患者免受抗癌药物的严重心脏毒性作用，这在许多情况下限制了其他有效疗法的使用。该项目的公共卫生意义在于，我们旨在保护患者免受抗癌药物的严重心脏毒性作用，这在许多情况下限制了其他有效疗法的使用。

DESCRIPTION (provided by applicant): The new approach of targeted cancer therapy has been received well, but an underlying theme needs to be addressed. Many of the proteins that are targeted for cancer therapy also have a major role in the heart. Our laboratory's long-term goals are to better understand erbB2 and HSP90 function in the heart, identify patients at risk for cardiac injury from cancer therapy, and develop new treatment strategies that can effectively treat cancer while also protecting the heart from the cancer therapeutic agents. We hypothesize that erbB2 is induced in the heart by oxidative stress, and that it also has a central role in protecting the heart from oxidative stress (including stress induced by doxorubicin therapy). Furthermore, we hypothesize that the chaperone HSP90 cooperates in this cellular protection by stabilizing the erbB2 protein in heart cells. Aim 1: Determine the role of oxidative stress and associated cell signaling to induce cardioprotection through erbB2 or HSP90 (protein or mRNA) and the role of NF-:2 using the following oxidative stress models: 1) H2O2, xanthine/xanthine oxidase and glutathione depletion in rat cardiomyocytes and in vivo glutathione depletion 2) diabetes cardiomyopathy, and 3) redox modulation with resveratrol or geranylgeranylacetone to prevent doxorubicin toxicity. Additionally, we will determine the role of free radical scavengers on erbB2 expression and the role of erbB2 pathway inhibition on cellular protection during oxidative stress. Aim 2: Determine whether the cardioprotective role of erbB2 is due to a reduction of cardiac oxidative stress. Here we aim to assess whether: 1) erbB2 pathway inhibition in cardiomyocytes (through anti-erbB2 or siRNA) results in increased oxidative stress and dysfunction in the mitochondria, and thus increased sensitivity to doxorubicin, 2) lapatinib induces cardiac oxidative stress and cell death in vivo, with or without doxorubicin therapy compared to cancer xenografts, 3) transgenic cardiac-specific over-expression of erbB2 protects from oxidative stress and mitochondrial dysfunction in two models of oxidative stress (doxorubicin-induced cardiomyopathy and streptozotocin-induced diabetes cardiomyopathy). Aim 3: Determine the cellular protective role of HSP90 as a chaperone of erbB2 protein in the heart. Here we aim to assess whether: 1) cardiac-specific over-expression of HSP90 in a transgenic mouse model reduces heart failure, cell death and oxidative stress via stabilization of erbB2 in two models: doxorubicin-induced heart toxicity or streptozotocin-induced diabetes cardiomyopathy; 2) inhibiting HSP90 protein expression or function increases cardiomyocyte death during doxorubicin therapy in vitro with siRNA or in vivo with 17AAG in mice with cancer xenografts, and 3) HSP90 inhibitor (17AAG) affects cardiac erbB2 levels in isolated hearts and inhibits heart function and mitochondrial function. PUBLIC HEALTH RELEVANCE: The public health significance of this project is that we aim to protect patients from severe cardiotoxic effects of anti-cancer drugs, which in many cases, limits the use of otherwise effective therapies. The public health significance of this project is that we aim to protect patients from severe cardiotoxic effects of anti-cancer drugs, which in many cases, limits the use of otherwise effective therapies.