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

• 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
• 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

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.

项目摘要 蒽环类药物化疗是治疗多种癌症的有效方法， 具有严重的心脏毒性阿霉素是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 心脏保护的重要性。我们已发表的工作已经确定细胞周期蛋白依赖性激酶2（CDK 2）作为一个关键的 蒽环类药物心脏毒性的介质。从机制上讲，CDK 2增强了叉头盒O 1（FOXO 1）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 根据这些发现，我们假设心脏CDK 2活性决定化疗敏感性（化疗敏感性） 在心脏。CDK 2最为人所知的是其在增殖细胞中的细胞周期进展中的经典作用，以及其活性 由参与细胞周期调控的多种蛋白质严格控制。由于心肌细胞是有丝分裂后的 细胞周期活性最低，仍有待确定CDK 2活性如何在心脏中调节 设置.有趣的是，我们的初步结果显示，CDK 2被CDK 7激活，但被CDK 7抑制。 视网膜母细胞瘤样2（RBL 2）。在本申请中，我们建议解决这些细胞的作用， 周期蛋白在心肌细胞凋亡和心脏化疗敏感性中的作用。该提案有三个具体目标： 1)确定CDK 7在DOX诱导的CDK 2活化和心肌细胞凋亡中的作用; 2）评估CDK 7在DOX诱导的CDK 2活化和心肌细胞凋亡中的作用。 CDK 7-CDK 2轴作为DOX心脏毒性的新药物靶点的可行性;以及3）确定RBL 2 调节CDK 2活性和心脏DOX敏感性。我们的方法是创新的，因为各种国家的- 将使用ART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 小鼠模型。本申请中建立的新机制将具有巨大的转化潜力， 可以为癌症治疗期间开发新的心脏保护策略奠定基础。