Signal Transduction in the Heart after Cancer Therapy

癌症治疗后心脏的信号转导

• 批准号: 7531445
• 负责人: KATHLEEN Louise GABRIELSON
• 金额: $ 41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531445
• 关键词: 17-(Allylamino)-17-demethoxygeldanamycin; Address; Affect; Animals; Antibodies; Antineoplastic Agents; Binding; Cancer Patient; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cell Death; Cells; Cessation of life; Clinical; Complication; Condition; Consensus Sequence; Cultured Cells; Data; Diabetes Mellitus; Doxorubicin; Free Radical Scavengers; Functional disorder; Genetic Transcription; Glutathione; Goals; HSP 90 inhibition; Heart; Heart failure; Heat-Shock Proteins 90; Hydrogen Peroxide; In Vitro; Injury; Laboratories; Ligands; Link; Malignant Neoplasms; Messenger RNA; Mitochondria; Modeling; Molecular; Molecular Chaperones; Mus; Neuregulins; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Proteins; Public Health; Publishing; Rattus; Resveratrol; Risk; Roche brand of trastuzumab; Role; Signal Transduction; Small Interfering RNA; Streptozocin; Stress; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Transgenic Organisms; Trastuzumab; Xanthine Oxidase; Xanthines; Xenograft procedure; base; cancer cell; cancer therapy; geranylgeranylacetone; heart cell; heart function; in vivo; inhibitor/antagonist; lapatinib; malignant breast neoplasm; mitochondrial dysfunction; mouse model; novel strategies; prevent; promoter; protein expression; small molecule; xanthine; 17-(Allylamino)-17-demethoxygeldanamycin; Address; Affect; Animals; Antibodies; Antineoplastic Agents; Binding; Cancer Patient; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cell Death; Cells; Cessation of life; Clinical; Complication; Condition; Consensus Sequence; Cultured Cells; Data; Diabetes Mellitus; Doxorubicin; Free Radical Scavengers; Functional disorder; Genetic Transcription; Glutathione; Goals; HSP 90 inhibition; Heart; Heart failure; Heat-Shock Proteins 90; Hydrogen Peroxide; In Vitro; Injury; Laboratories; Ligands; Link; Malignant Neoplasms; Messenger RNA; Mitochondria; Modeling; Molecular; Molecular Chaperones; Mus; Neuregulins; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Proteins; Public Health; Publishing; Rattus; Resveratrol; Risk; Roche brand of trastuzumab; Role; Signal Transduction; Small Interfering RNA; Streptozocin; Stress; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Transgenic Organisms; Trastuzumab; Xanthine Oxidase; Xanthines; Xenograft procedure; base; cancer cell; cancer therapy; geranylgeranylacetone; heart cell; heart function; in vivo; inhibitor/antagonist; lapatinib; malignant breast neoplasm; mitochondrial dysfunction; mouse model; novel strategies; prevent; promoter; protein expression; small molecule; xanthine

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.

描述（由申请人提供）：靶向癌症疗法的新方法已经很好地接受，但是需要解决一个基本主题。许多用于癌症治疗的蛋白质在心脏中也具有重要作用。我们的实验室的长期目标是更好地了解心脏中的ERBB2和HSP90功能，确定患有心脏损伤的患者受到癌症治疗的风险，并制定可以有效治疗癌症的新治疗策略，同时还可以保护心脏免受癌症治疗剂的侵害。我们假设ERBB2是通过氧化应激在心脏中诱导的，并且它在保护心脏免受氧化应激（包括由阿霉素治疗引起的胁迫）方面也具有核心作用。此外，我们假设伴侣HSP90通过稳定心脏细胞中的ERBB2蛋白来在这种细胞保护中合作。 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心肌病和3）用白藜芦醇或黄烷基果仁酮的氧化还原调节，以防止阿霉素毒性。此外，我们将确定自由基清除剂对ERBB2表达的作用以及ERBB2途径在氧化应激过程中抑制细胞保护的作用。 AIM 2：确定ERBB2的心脏保护作用是否是由于心脏氧化应激的减少所致。 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）ERBB2的转基因心脏特异性过表达可保护两种氧化应激模型中的氧化应激和线粒体功能障碍（阿霉素诱导的心肌病和链链球菌素诱导的糖尿病性心肌病）。 AIM 3：确定HSP90作为心脏中ERBB2蛋白的伴侣的细胞保护作用。在这里，我们的目的是评估：1）在转基因小鼠模型中HSP90的心脏特异性过表达是否通过在两个模型中稳定ERBB2来减少心力衰竭，细胞死亡和氧化应激：阿霉素诱导的心脏毒性或链球菌诱导的糖尿病诱导的糖尿病性糖尿病； 2）抑制HSP90蛋白质表达或功能会在阿霉素治疗期间与siRNA或体内在患有癌症异种移植的小鼠中的17AAG体外增加心肌细胞死亡，而3）HSP90抑制剂（17AAG）在孤立的心脏和抑制性心脏功能和抑制性心脏功能和抑制性的心脏和抑制作用。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，在许多情况下，这限制了使用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，在许多情况下，这种影响限制了使用原本有效的疗法。