权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10280044
负责人：
Jianxin Sun
金额：
$ 52.66万
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/10280044
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

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.

项目总结