Promoting chemoresistance in the heart

促进心脏的化疗耐药性

基本信息

批准号：
9281936
负责人：
Zhaokang Cheng
金额：
$ 24.9万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9281936
关键词：
Adult Adverse effects Anthracyclines Antibiotics Apoptosis Apoptotic Attenuated Biological Assay CDK2 gene CDKN1A gene Cardiac Myocytes Cardiomyopathies Cardiotoxicity Cardiovascular Diseases Cause of Death Cell Cycle Cell Death Cells Cessation of life Congestive Heart Failure Cullin Proteins Cyclin-Dependent Kinase Inhibitor Data Daunorubicin Doxorubicin Embryo Event Family Family member Focal Adhesion Kinase 1 Gene Transfer Genetic Polymorphism Genetic Transcription Genotoxic Stress Goals Heart Heart failure Human Hypertrophy Imatinib In Vitro Laboratories Lead Life MYB gene Mediating Mentors Mitochondria Mus Muscle Cells Myocardial Myocardial dysfunction Myocardial tissue Oxidative Stress Pathway interactions Patients Pharmaceutical Preparations Phase Phosphotransferases Preventive Proto-Oncogene Proteins c-myb Regulation Resistance Risk Role Signal Transduction System Testing Therapeutic Training Transcriptional Regulation Transgenic Organisms Tyrosine Kinase Inhibitor Ubiquitination Work base chemotherapeutic agent chemotherapy chromatin immunoprecipitation gain of function gene therapy in vivo inhibitor/antagonist insight kinase inhibitor knock-down mortality novel novel therapeutic intervention prevent protein degradation research study response screening transcription factor ubiquitin-protein ligase ultraviolet irradiation

项目摘要

Life-threatening cardiomyopathy and heart failure are common side effects of a number of chemotherapy drugs, such as the anthracycline family of antibiotics (e.g. doxorubicin, daunorubicin) and the tyrosine kinase inhibitors (e.g. imatinib, sunitinib). Doxorubicin (DOX) is one of the most frequently used chemotherapeutic agents and the most well-known cause of chemotherapy-induced cardiac toxicity. Therefore I choose to evaluate chemoresistance against DOX in this proposal using mice and primary cardiomyocytes. DOX cardiotoxicity has been attributed to oxidative and genotoxic stress-induced apoptotic cell death of cardiomyocytes. Therefore, protection of myocardial tissue from apoptosis is central to prevent DOX-induced cardiomyopathy. Although DOX cardiotoxicity has been extensively studied, successful therapeutic strategies are still unavailable. Previous work from the laboratory of my mentor, Dr. Joan Taylor, has identified focal adhesion kinase (FAK) as a critical protective molecule against myocyte apoptosis in the heart. Most recently, I demonstrated that FAK-dependent protection against DOX cardiotoxicity was mediated by the cyclindependent kinase (CDK) inhibitor (CDKI) p21Cip1/WAF1 (p21). Previous studies regarding CDKIs including p21 in cardiomyocytes have been largely focused on proliferation and hypertrophy. Here, my results support a novel function of p21 in regulation of chemoresistance and apoptosis in the heart. As an extension of this work, my long-term goal is to establish participation of CDKIs in cardiomyocyte survival signaling. Working towards this goal, the objective in my K99/R00 application is to determine the regulation of p21 in cardiomyocytes and further explore p21-mediated protection against DOX cardiotoxicity. The central hypothesis is that myocardial p21 levels determine resistance to DOX-induced myocyte apoptosis and cardiomyopathy. I plan to test the central hypothesis by accomplishing the following three specific aims: 1) Investigate the expression and degradation of p21 in cardiomyocytes [mentored]; 2) Define mechanisms of p21-mediated resistance to DOX cardiotoxicity [independent]; and 3) Demonstrate protection by p21 against DOX-induced cardiomyopathy [independent].

危及生命的心肌病和心力衰竭是许多化疗药物的常见副作用，例如蒽环类抗生素（例如阿霉素、柔红霉素）和酪氨酸激酶抑制剂（例如伊马替尼、舒尼替尼）。阿霉素（DOX）是最常用的化疗药物之一药物和化疗引起的心脏毒性的最著名原因。因此我选择在本提案中使用小鼠和原代心肌细胞评估对 DOX 的化疗耐药性。阿霉素心脏毒性归因于氧化和基因毒性应激诱导的细胞凋亡心肌细胞。因此，保护心肌组织免于凋亡对于预防 DOX 诱导的细胞凋亡至关重要。心肌病。尽管 DOX 心脏毒性已得到广泛研究，但成功的治疗策略仍然不可用。我的导师琼·泰勒博士的实验室之前的工作已经确定了焦点粘附激酶（FAK）是心脏中对抗心肌细胞凋亡的关键保护分子。最近，我证明 FAK 依赖性的针对 DOX 心脏毒性的保护作用是由细胞周期蛋白依赖性介导的激酶 (CDK) 抑制剂 (CDKI) p21Cip1/WAF1 (p21)。先前关于 CDKI 的研究，包括 p21 心肌细胞主要集中于增殖和肥大。在这里，我的结果支持一部小说 p21 在调节心脏化疗耐药和细胞凋亡中的功能。作为这项工作的延伸，我的长期目标是确定 CDKI 参与心肌细胞存活信号传导。朝这个方向努力我的 K99/R00 应用程序的目标是确定心肌细胞中 p21 的调节以及进一步探索 p21 介导的针对 DOX 心脏毒性的保护作用。中心假设是心肌 p21 水平决定对 DOX 诱导的心肌细胞凋亡和心肌病的抵抗力。我计划测试通过实现以下三个具体目标来提出中心假设：1）研究表达式和心肌细胞中 p21 的降解 [指导]； 2) 定义p21介导的DOX耐药机制心脏毒性[独立]； 3) 证明 p21 对 DOX 诱导的心肌病具有保护作用 [独立的]。