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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要阿京霉素（DOX）是一种蒽环类化疗，是一种公认且高效的化学疗法通常用于治疗多种癌症类型的药物，但其使用受心脏毒性的限制。 DOX患者疗法通常会出现延迟的心肌病，因此没有有效的疗法。分子这种药物毒性的机制仍然很少理解，并且可能是多因素的。 DNA损坏，线粒体功能障碍，p53激活和多余的心肌细胞凋亡是造成这种情况的主要因素 DOX诱导的心脏毒性的发病机理，但是药物策略是否可以轻松起作用在接受DOX治疗的患者中，尚未发现所有这些事件。我们的实验室在研究核接收器4A（NR4A）生物学在心血管中的作用方面有很长的记录稳态和疾病。在最近的工作中，我们产生了大量证据来支持 NR4A接收器的家庭成员NUR77的心脏表达的新颖概念，扮演因果关系在DOX心肌病的发病机理中的作用。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降低了2） NUR77有效防止DOX诱导心脏功能障碍，心肌细胞凋亡和纤维化。此外，我们已经将DNA拓扑异构酶IIβ结合蛋白1（TOPBP1）确定为NUR77的关键下游效应子在心脏中，发现其表达在经过DOX处理的心脏中大大降低。更重要的是，我们的初步数据表明NUR77可防止通过诱导的TOPBP1-昆虫酶IIβ的心脏毒性（top2β）相互作用，这反过心。这些数据导致我们假设NUR77是重要的心脏保护剂，并且 NUR77的靶向激活可以有效防止DOX诱导的心肌病，而最小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。 AIM 1将执行通过使用NUR77心脏特异性基因敲除小鼠（CNUR77-KO）来确定是否是否确定功能丧失研究通过增强的凋亡，纤维化，和心脏发炎。 AIM 2将确定NUR77表现出的基本机制对DOX诱导的心脏损伤的心脏保护作用。心脏特异性TOPBP1转基因和淘汰小鼠将用于评估TOPBP1对鼠标NUR77发射的心脏保护的贡献 DOX心脏毒性的模型。 AIM 3将研究NUR77的药物激活是否具有容量阻止DOX心肌病，而没有损害药物的抗癌活性。成功完成这些目标将指导我们开发新的治疗剂，以防止抗癌药物的选择性毒性心。这种靶向人类的预测效用和可行性有利于翻译潜力和拟议研究的最终影响。