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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：
10558622
负责人：
Zhaokang Cheng
金额：
$ 48.49万
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/10558622
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 Cell Proliferation 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 Induction of Apoptosis Injury Knockout Mice Life Expectancy Mediating Mediator Modeling Modernization Morbidity - disease rate Mus Muscle Cells Phenotype Phosphorylation Phosphotransferases Population Proteins Publishing RBL2 gene Reporting Repression Research Role System Testing Topoisomerase Toxic effect Treatment-Related Cancer United States Work cancer therapy cancer type cardioprotection chemotherapy effective therapy gain of function heart damage heart disease risk improved in vivo innovation loss of function mortality mouse model new therapeutic target novel patient prognosis postmitotic 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.

项目总结