Cell cycle proteins as key regulators of cardiac chemosensitivity

细胞周期蛋白作为心脏化疗敏感性的关键调节因子

基本信息

批准号：
10353398
负责人：
Zhaokang Cheng
金额：
$ 48.66万
依托单位：
WASHINGTON STATE 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：
2021-02-16 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10353398
关键词：
Ablation Adult Allografting Anthracycline Antineoplastic Agents Apoptosis Apoptotic Biological Models Biological Process Birth CDK2 gene Cancer Patient Cancer Survivor Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Cell Cycle Cell Cycle Progression Cell Cycle Proteins Cell Cycle Regulation Cells Cessation of life Chemotherapy-Oncologic Procedure DNA Damage DNA Double Strand Break Data Doxorubicin Foundations Genetic Transcription Genetically Engineered Mouse Heart Heart failure Immunocompetent In Vitro Injury Knockout Mice Lead Life Expectancy Mediating Mediator of activation protein Modeling Modernization Morbidity - disease rate Mus Muscle Cells Phenotype Phosphorylation Phosphotransferases Population Proliferating Proteins Publishing RBL2 gene Reporting Research Role System Testing Topoisomerase Toxic effect Treatment-Related Cancer United States Work base cancer therapy cancer type cardioprotection chemotherapy effective therapy gain of function heart damage heart disease risk improved in vivo innovation mortality new therapeutic target novel patient prognosis prevent pro-apoptotic protein protein expression success translational potential tumor

项目摘要

PROJECT SUMMARY Anthracycline-based chemotherapy, an effective treatment for many types of cancer, has long been associated with substantial cardiotoxicity. As one of the most commonly used anthracycline anticancer agent, doxorubicin (DOX) induces DNA damage and subsequent cardiomyocyte apoptosis, eventually resulting in cardiomyopathy and heart failure. Therefore, understanding the mechanisms of DOX-induced apoptosis is of paramount importance for cardioprotection. Our published work has identified cyclin-dependent kinase 2 (CDK2) as a critical mediator of anthracycline cardiotoxicity. Mechanistically, CDK2 augments forkhead box O1 (FOXO1)-dependent expression of Bim, a pro-apoptotic protein indispensable for DOX-induced cardiomyocyte apoptosis. Based on these findings, we hypothesize that cardiac CDK2 activity determines chemotherapy sensitivity (chemosensitivity) in the heart. CDK2 is best known for its classical role in cell cycle progression in proliferating cells, and its activity is tightly controlled by multiple proteins involved in cell cycle regulation. Since cardiomyocytes are postmitotic cells with minimal cell cycle activity, it remains to be determined how CDK2 activity is regulated in the cardiac settings. Interestingly, our preliminary results revealed that CDK2 was activated by CDK7, but inhibited by retinoblastoma-like 2 (RBL2) in cardiomyocytes. In this application, we propose to tackle the roles of these cell cycle proteins in cardiomyocyte apoptosis and cardiac chemosensitivity. This proposal has three Specific Aims: 1) Define the role of CDK7 in DOX-induced CDK2 activation and cardiomyocyte apoptosis; 2) Assess the feasibility of the CDK7-CDK2 axis as a new drug target for DOX cardiotoxicity; and 3) Determine how RBL2 regulates CDK2 activity and cardiac DOX sensitivity. Our approach is innovative because various state-of-the- art systems will be used, including immunocompetent mouse tumor allograft model and genetically engineered mouse models. The novel mechanisms established in this application will have great translational potential, and could lay the foundation for developing new cardioprotective strategies during cancer treatment.

项目概要基于蒽环类药物的化疗是多种癌症的有效治疗方法，长期以来一直与具有显着的心脏毒性。阿霉素作为最常用的蒽环类抗癌药物之一 (DOX) 诱导 DNA 损伤和随后的心肌细胞凋亡，最终导致心肌病和心力衰竭。因此，了解DOX诱导细胞凋亡的机制至关重要对心脏保护的重要性。我们发表的工作已确定细胞周期蛋白依赖性激酶 2 (CDK2) 是一个关键的蒽环类心脏毒性介质。从机制上讲，CDK2 增强了叉头盒 O1 (FOXO1) 依赖性 Bim 的表达，Bim 是 DOX 诱导的心肌细胞凋亡所必需的促凋亡蛋白。基于这些发现，我们假设心脏CDK2活性决定化疗敏感性（chemosensitivity）在心里。 CDK2 因其在增殖细胞的细胞周期进展中的经典作用及其活性而闻名受到参与细胞周期调节的多种蛋白质的严格控制。由于心肌细胞处于有丝分裂后细胞具有最小的细胞周期活性，但 CDK2 活性在心脏中是如何调节的仍有待确定设置。有趣的是，我们的初步结果表明，CDK2 被 CDK7 激活，但被 CDK7 抑制。心肌细胞中的视网膜母细胞瘤样 2 (RBL2)。在此应用中，我们建议解决这些细胞的角色心肌细胞凋亡和心脏化疗敏感性中的循环蛋白。该提案有三个具体目标： 1）明确CDK7在DOX诱导的CDK2激活和心肌细胞凋亡中的作用； 2) 评估 CDK7-CDK2轴作为DOX心脏毒性新药物靶点的可行性； 3) 确定 RBL2 如何调节 CDK2 活性和心脏 DOX 敏感性。我们的方法是创新的，因为各种最新状态将使用艺术系统，包括免疫活性小鼠肿瘤同种异体移植模型和基因工程鼠标模型。本申请中建立的新机制将具有巨大的转化潜力，并且可以为癌症治疗期间开发新的心脏保护策略奠定基础。