Mechanisms of cardiac chemosensitivity

心脏化疗敏感性的机制

基本信息

批准号：
10002633
负责人：
Zhaokang Cheng
金额：
$ 44.91万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10002633
关键词：
Ablation Adolescent Adriamycin PFS Adult Age Anthracyclines Antineoplastic Agents Apoptosis Apoptotic BIM Bcl-2-binding protein Biological Assay CDK2 gene Cancer Control Cancer Patient Cancer Survivor Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Cause of Death Cell Cycle Cell Cycle Arrest Cell Death Cessation of life Child Cyclin-Dependent Kinase Inhibitor Cytotoxic Chemotherapy DNA biosynthesis Data Dissociation Doxorubicin FOXO1A gene Family Foundations G1 Phase G1/S Transition Genes Genetic Transcription Growth Heart In Vitro Injury Iron Lead Malignant Neoplasms Mediating Mediator of activation protein Mitochondria Modernization Molecular Morbidity - disease rate Muscle Cells Myocardial Myocardial dysfunction Names Pathogenesis Pathway interactions Patients Preventive RBL2 gene Regulation Reporter Repression Resistance Retinoblastoma Protein Risk Risk Factors Role S Phase System Testing Therapeutic Tissues Topoisomerase Treatment-Related Cancer United States Work age group base cancer diagnosis cancer therapy cardiogenesis cardioprotection chemotherapy chromatin immunoprecipitation experimental study gain of function heart damage high risk in vivo insight mortality novel overexpression patient population prevent pro-apoptotic protein response screening side effect transcription factor treatment strategy

项目摘要

PROJECT SUMMARY Advances in cancer diagnosis and therapeutics over the last three decades have greatly reduced cancer mortality rates. However, this benefit was accompanied by a paradoxical rise of treatment-related cardiotoxicity, which has become the most common non-cancer cause of death among the 15.5 million cancer survivors in the United States. The most severe form of cardiotoxicity is Type I cardiotoxicity, which is predominantly caused by the anthracycline family of anticancer agents including doxorubicin (DOX, trade name: Adriamycin) due to induction of myocyte death. Younger age at treatment is a major risk factor for developing anthracycline cardiotoxicity. Most recent findings suggested that chemosensitivity in young tissues was caused by higher levels of apoptosis in response to cytotoxic chemotherapies. A key feature distinguishing children from adults is that the heart is still growing with active DNA synthesis and significant cell cycle activity. We hypothesize that elevated cell cycle activity in cardiomyocytes enhances cardiac chemosensitivity by accelerating apoptosis following DOX exposure. In support of this hypothesis, we have shown that expression of p21, a Cip/Kip family cyclin-dependent kinase (CDK) inhibitor that arrests the cell cycle, protected against DOX-induced apoptotic death of cardiomyocytes. By contrast, activation of CDK2 exacerbated DOX-induced cardiomyocyte apoptosis and promoted expression of the pro-apoptotic protein Bim. Importantly, DOX treatment induced CDK2 activation in vitro and in vivo, suggesting that CDK2 activation may represent a key mechanism underlying DOX-induced myocyte apoptosis and cardiotoxicity. Based on these findings, we propose to further tackle the role of cell cycle machinery in cardiomyocyte apoptosis and cardiac chemosensitivity by pursuing the following three Specific Aims: 1) Define the mechanisms of CDK2-mediated DOX cardiotoxicity; 2) Investigate the regulation of CDK2 activity in cardiomyocytes; 3) Identify the common regulator for cell cycle activity and cardiac chemosensitivity. The proposed studies will have the potential to uncover novel mechanisms underlying cardiac chemosensitivity, and may lay the foundation for developing new treatment strategies against anthracycline cardiomyopathy.

项目概要过去三十年癌症诊断和治疗的进步大大减少了癌症的发生死亡率。然而，这种益处伴随着与治疗相关的心脏毒性的矛盾上升，它已成为美国 1550 万癌症幸存者中最常见的非癌症死亡原因美国。最严重的心脏毒性是 I 型心脏毒性，主要由以下原因引起：蒽环类抗癌药物家族，包括阿霉素（DOX，商品名：阿霉素），由于诱导心肌细胞死亡。治疗时年龄较小是发生蒽环类药物心脏毒性的主要危险因素。最新发现表明年轻组织的化疗敏感性是由较高水平的细胞凋亡引起的细胞毒性化疗。儿童与成人的一个关键特征是心脏仍在发育活跃的 DNA 合成和显着的细胞周期活性。我们假设细胞周期活性升高心肌细胞在 DOX 暴露后通过加速细胞凋亡来增强心脏化疗敏感性。在为了支持这一假设，我们证明了 p21（一种 Cip/Kip 家族细胞周期蛋白依赖性激酶）的表达 (CDK) 抑制剂可阻止细胞周期，防止 DOX 诱导的心肌细胞凋亡。经过相反，CDK2的激活加剧了DOX诱导的心肌细胞凋亡并促进了促凋亡蛋白 Bim。重要的是，DOX 治疗在体外和体内诱导 CDK2 激活，表明 CDK2 激活可能是 DOX 诱导心肌细胞凋亡的关键机制和心脏毒性。基于这些发现，我们建议进一步解决细胞周期机制在通过追求以下三个具体目标来控制心肌细胞凋亡和心脏化疗敏感性：1) 定义 CDK2介导的DOX心脏毒性机制； 2）研究CDK2活性的调节心肌细胞； 3) 确定细胞周期活动和心脏化学敏感性的共同调节因子。这拟议的研究将有可能揭示心脏化学敏感性的新机制，并且可能为开发针对蒽环类心肌病的新治疗策略奠定基础。