Prevention of anthracycline-induced cardiotoxicity by Nur77 activation

通过 Nur77 激活预防蒽环类药物引起的心脏毒性

• 批准号: 10452543
• 负责人: Jianxin Sun
• 金额: $ 52.83万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-16 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10452543
• 关键词: Adult; Anthracycline; Antineoplastic Agents; Apoptosis; Attenuated; Behavior; Binding Proteins; Biology; Cancer Model; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotonic Agents; Cardiotoxicity; Cardiovascular system; Complex; DNA Damage; DNA Topoisomerases; Data; Development; Disease; Doxorubicin; Doxorubicin-DNA Complex; Drug toxicity; Drug usage; Event; Exhibits; Family member; Fibrosis; Future; Genomic DNA; Heart; Heart Injuries; Heart failure; Homeostasis; Human; In Vitro; Inflammation; Injury; Knockout Mice; Knowledge; Laboratories; Life; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Myocardial dysfunction; Nuclear Receptors; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Play; Pre-Clinical Model; Prevention; Process; Role; TP53 gene; Testing; Therapeutic Agents; Tissues; Topoisomerase; Toxic effect; Transgenic Mice; Work; anti-cancer; anticancer activity; cancer cell; cancer therapy; cancer type; cardioprotection; chemotherapy; clinically relevant; effective therapy; heart function; in vivo; loss of function; mitochondrial dysfunction; mouse model; novel; novel therapeutics; overexpression; preservation; prevent; receptor; therapeutic target; translational potential

Project summary Doxorubicin (Dox), an anthracycline chemotherapeutic, is a well-established and highly effective chemotherapy drug commonly used to treat multiple cancer types, but its use is limited by cardiotoxicity. Patients with Dox therapy often develop delayed cardiomyopathy for which no effective therapies exist. The molecular mechanisms of this drug toxicity remain poorly understood and are likely to be multifactorial. DNA damage, mitochondrial dysfunction, p53 activation, and excessive cardiomyocyte apoptosis are major contributors to the pathogenesis of Dox-induced cardiac toxicity, but whether a pharmacological strategy can simultaneously work to reverse all of these events in patients that receive Dox treatment has yet to be uncovered. Our laboratories have a long track record in studying the role of nuclear receptor 4A (NR4A) biology in cardiovascular homeostasis and disease. In recent work, we have generated a significant body of evidence to support the novel concept that reduced cardiac expression of Nur77, a family member of NR4A receptors, plays a causal role in the pathogenesis of Dox cardiomyopathy. We have found that 1) Cardiac expression of Nur77 is significantly reduced in Dox treated cardiomyocytes and hearts and that 2) Cardiac specific overexpression of Nur77 effectively prevents Dox induced cardiac dysfunction, cardiomyocyte apoptosis, and fibrosis. In addition, we have identified DNA topoisomerase IIβ-binding protein 1 (TopBP1) as a key downstream effector of Nur77 in the heart, and have found that its expression is substantially reduced in Dox-treated hearts. More importantly, our preliminary data indicate that Nur77 prevents cardiac toxicity by inducing TopBP1-topoisomerase IIβ (Top2β) interactions, which in turn effectively shields Top2β/genomic DNA from Dox-induced damage in the heart. These data led us to hypothesize that Nur77 serves as an important cardioprotective agent and that targeted activation of Nur77 can effectively prevent Dox-induced cardiomyopathy while having minimal to no effects on its anti-cancer behaviors. We will test this hypothesis in the following three aims. Aim 1 will perform loss-of-function studies by employing Nur77 cardiac specific knockout mice (cNur77-KO) to determine whether cardiac specific deletion of Nur77 exacerbates Dox-induced cardiotoxicity through enhanced apoptosis, fibrosis, and inflammation in the heart. Aim 2 will determine the underlying mechanisms by which Nur77 exhibits its cardioprotective effects against Dox-induced cardiac injury. Cardiac specific TopBP1 transgenic and knockout mice will be used to assess the contribution of TopBP1 to the Nur77-initiated cardiac protection in mouse models of Dox cardiotoxicity. Aim 3 will study whether pharmacological activation of Nur77 holds the capacity to block Dox cardiomyopathy without compromising anti-cancer activity of the drug. Successful completion of these aims will guide us to develop new therapeutic agents to prevent selective toxicity of anticancer drugs to the heart. The predicted utility and feasibility of such targeting in humans favors the translational potential and ultimate impact of the proposed studies.

项目概要 阿霉素 (Dox) 是一种蒽环类化疗药物，是一种成熟且高效的化疗药物 通常用于治疗多种癌症类型的药物，但其使用受到心脏毒性的限制。服用阿霉素的患者 治疗经常会发展为迟发性心肌病，而目前尚无有效的治疗方法。分子 这种药物毒性的机制仍然知之甚少，并且可能是多因素的。 DNA损伤， 线粒体功能障碍、p53 激活和过度心肌细胞凋亡是导致 Dox 引起的心脏毒性的发病机制，但药理学策略是否可以同时发挥作用 尚不清楚如何在接受 Dox 治疗的患者中逆转所有这些事件。我们的实验室 在研究核受体 4A (NR4A) 生物学在心血管中的作用方面拥有长期的记录 体内平衡和疾病。在最近的工作中，我们产生了大量的证据来支持 新概念认为减少 Nur77（NR4A 受体家族成员）的心脏表达起着因果作用 Dox 心肌病发病机制中的作用。我们发现 1) Nur77 的心脏表达是 在 Dox 处理的心肌细胞和心脏中显着减少，并且 2) 心脏特异性过表达 Nur77 能有效预防 Dox 引起的心脏功能障碍、心肌细胞凋亡和纤维化。此外， 我们已经确定 DNA 拓扑异构酶 IIβ 结合蛋白 1 (TopBP1) 是 Nur77 的关键下游效应子 并发现在 Dox 处理的心脏中其表达大大减少。更重要的是， 我们的初步数据表明，Nur77 通过诱导 TopBP1-拓扑异构酶 IIβ 来预防心脏毒性 (Top2β) 相互作用，进而有效地保护 Top2β/基因组 DNA 免受 Dox 诱导的损伤 心。这些数据使我们推测 Nur77 是一种重要的心脏保护剂，并且 靶向激活 Nur77 可以有效预防 Dox 诱发的心肌病，同时几乎没有影响 对其抗癌行为的影响。我们将在以下三个目标中检验这一假设。目标 1 将执行 通过使用 Nur77 心脏特异性基因敲除小鼠 (cNur77-KO) 进行功能丧失研究，以确定是否 Nur77 的心脏特异性缺失通过增强细胞凋亡、纤维化、 和心脏炎症。目标 2 将确定 Nur77 展示其功能的基本机制 对 Dox 引起的心脏损伤的心脏保护作用。心脏特异性 TopBP1 转基因和敲除 将使用小鼠来评估 TopBP1 对 Nur77 启动的小鼠心脏保护的贡献 Dox心脏毒性模型。目标 3 将研究 Nur77 的药理激活是否具有能力 阻断 Dox 心肌病而不损害药物的抗癌活性。顺利完成 这些目标将指导我们开发新的治疗药物，以防止抗癌药物的选择性毒性 心脏。这种针对人类的预期效用和可行性有利于转化潜力和 拟议研究的最终影响。