Signal Transduction in the Heart after Cancer Therapy

癌症治疗后心脏的信号转导

• 批准号: 8274732
• 负责人: KATHLEEN Louise GABRIELSON
• 金额: $ 40.59万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274732
• 关键词: 17-(Allylamino)-17-demethoxygeldanamycin; Address; Affect; Animals; Antibodies; Antineoplastic Agents; Binding; Cancer Patient; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Clinical; Complication; Consensus Sequence; 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 Mice; Transgenic Organisms; Trastuzumab; Xanthine Oxidase; Xanthines; Xenograft procedure; base; cancer cell; cancer therapy; effective therapy; geranylgeranylacetone; heart cell; heart function; in vivo; inhibitor/antagonist; lapatinib; malignant breast neoplasm; mitochondrial dysfunction; mouse model; novel strategies; prevent; promoter; protein expression; protein function; small molecule; treatment strategy

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-¿¿ 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. 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.

靶向癌症治疗的新方法已广受好评，但需要明确一个基本主题 许多用于癌症治疗的蛋白质在心脏中也发挥着重要作用。 实验室的长期目标是更好地了解 erbB2 和 HSP90 在心脏中的功能，识别患者 面临癌症治疗导致心脏损伤的风险，并开发新的治疗策略，可以有效治疗 我们发现 erbB2 是抗癌药物，同时还能保护心脏免受癌症治疗药物的侵害。 氧化应激在心脏中引起，并且它在保护心脏免受氧化应激方面也具有核心作用 氧化应激（包括阿霉素治疗引起的应激）。 伴侣 HSP90 通过稳定心脏中的 erbB2 蛋白来配合这种细胞保护 目标 1：确定氧化应激和相关细胞信号传导对诱导心脏保护的作用。 通过 erbB2 或 HSP90（蛋白质或 mRNA）和 NF-¿ 的作用¿使用以下氧化应激模型： 1) 大鼠心肌细胞中的H2O2、黄嘌呤/黄嘌呤氧化酶和谷胱甘肽消耗以及体内谷胱甘肽 2) 糖尿病心肌病，以及 3) 用白藜芦醇或香叶基香叶基丙酮进行氧化还原调节 此外，我们将确定自由基清除剂对 erbB2 的作用。 erbB2 通路抑制对氧化应激期间细胞保护的表达和作用目标 2： 确定 erbB2 的心脏保护作用是否是由于减少心脏氧化应激所致。 旨在评估是否：1) 心肌细胞中的 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) 与使用或不使用阿霉素治疗相比，拉帕替尼在体内诱导心脏氧化应激和细胞死亡 对于癌症异种移植物，3) erbB2 转基因心脏特异性过度表达可防止氧化应激 和线粒体功能障碍在两种氧化应激模型（阿霉素诱导的心肌病和 目标 3：确定 HSP90 的细胞保护作用。 心脏中 erbB2 蛋白的伴侣蛋白。在这里，我们的目的是评估是否：1) 心脏特异性过度表达。 转基因小鼠模型中的 HSP90 通过稳定 HSP90 来减少心力衰竭、细胞死亡和氧化应激 erbB2 在两种模型中的作用：阿霉素诱导的心脏毒性或链脲佐菌素诱导的糖尿病心肌病 2) 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 体外使用 siRNA 或体内使用 17AAG 在癌症异种移植小鼠中，以及 3) HSP90 抑制剂 (17AAG) 影响 心脏 erbB2 水平在离体心脏中并抑制心脏功能和线粒体功能。 该项目的健康意义在于，我们的目标是保护患者免受严重的心脏毒性作用 抗癌药物，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的目标是保护患者免受严重心脏毒性作用。 抗癌药物在许多情况下限制了其他有效疗法的使用。

项目成果

ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity.

ErbB2 过度表达可上调抗氧化酶，降低活性氧的基础水平，并防止阿霉素心脏毒性。

• DOI: 10.1152/ajpheart.00517.2014
• 发表时间: 2015-08-07
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Frances Belmonte;Samarjit Das;Polina Sysa;V. Sivakumaran;Brian A. Stanley;Xin Guo;N. Paolocci;M. Aon;M. Nagane;P. Kuppusamy;C. Steenbergen;K. Gabrielson
• 通讯作者: K. Gabrielson

Echocardiographic Characterization of a Murine Model of Hypertrophic Obstructive Cardiomyopathy Induced by Cardiac-specific Overexpression of Epidermal Growth Factor Receptor 2.

表皮生长因子受体 2 心脏特异性过度表达诱导的肥厚性梗阻性心肌病小鼠模型的超声心动图表征。

• DOI: 10.1093/nar/gkz949
• 发表时间: 2024-09-14
• 期刊: Comparative medicine
• 影响因子: 0.8
• 作者: Lars L. Sorensen;D. Bedja;Polina Sysa;Hongyun Liu;A. Maxwell;Xu Yi;Iraklis Pozios;N. Olsen;T. Abraham;Roselle M. Abraham;K. Gabrielson
• 通讯作者: K. Gabrielson