Cell cycle proteins as key regulators of cardiac chemosensitivity

项目总结 以蒽环类药物为基础的化疗是许多类型癌症的有效治疗方法，长期以来一直被认为是 对心脏有很大的毒性。作为最常用的抗癌药物之一，阿霉素 (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。我们已发表的研究发现细胞周期蛋白依赖的蛋白2(CDK2)是一种关键的 蒽环类药物心脏毒性的中介物。从机制上讲，CDK2增加了叉头盒O1(FOXO1)依赖的 DOX诱导心肌细胞凋亡所必需的促凋亡蛋白Bim的表达。基于 这些发现，我们假设心脏cdk2活性决定化疗敏感性(化疗敏感性)。 在内心深处。CDK2最为人所知的是它在细胞周期进程中的经典作用，即增殖细胞，以及它的活性 受到多种参与细胞周期调控的蛋白质的严格控制。因为心肌细胞是有丝分裂后的 细胞周期活性最低的细胞，cdk2活性如何在心脏中被调节仍有待确定。 设置。有趣的是，我们的初步结果显示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)。在本应用程序中，我们建议解决这些单元的角色 循环蛋白在心肌细胞凋亡和心脏化疗敏感性中的作用这项建议有三个具体目标： 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心脏毒性的新药物靶点的可行性；以及3)决定RBL2如何 调节CDK2活性和心脏对DOX的敏感性。我们的方法是创新的，因为各种最新的 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 老鼠模型。在这项申请中建立的新机制将具有巨大的翻译潜力，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。

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.