Promoting chemoresistance in the heart

促进心脏的化疗耐药性

• 批准号: 8831001
• 负责人: Zhaokang Cheng
• 金额: $ 8.78万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8831001
• 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; Cyclin-Dependent Kinases; 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; 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; mortality; novel; novel therapeutics; prevent; protein degradation; research study; response; screening; transcription factor; ubiquitin-protein ligase; ultraviolet irradiation

DESCRIPTION (provided by applicant): PROJECT SUMMARY 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 cyclin- dependent 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].

描述（由申请人提供）：项目总结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，如蒽环类抗生素家族（如多柔比星、柔红霉素）和酪氨酸激酶抑制剂（如伊马替尼、舒尼替尼）。阿霉素（DOX）是最常用的化疗药物之一，也是化疗诱导心脏毒性的最常见原因。因此，我选择使用小鼠和原代心肌细胞来评估对DOX的化学抗性。DOX心脏毒性归因于心肌细胞的氧化和遗传毒性应激诱导的细胞凋亡。因此，保护心肌组织免于凋亡是预防DOX诱导的心肌病的核心。虽然DOX心脏毒性已被广泛研究，但成功的治疗策略仍然不可用。我的导师Joan Taylor博士的实验室以前的工作已经确定了粘着斑激酶（FAK）是心脏中防止心肌细胞凋亡的关键保护分子。最近，我证明了FAK依赖性的对DOX心脏毒性的保护作用是由细胞周期蛋白依赖性激酶（CDK）抑制剂（CDKI）p21 Cip 1/WAF 1（p21）介导的。先前关于心肌细胞中包括p21的CDKI的研究主要集中在增殖和肥大上。在这里，我的研究结果支持p21在调节心脏的化疗耐药性和细胞凋亡中的新功能。作为这项工作的延伸，我的长期目标是建立CDKIs参与心肌细胞存活信号传导。为了实现这一目标，我的K99/R 00申请的目标是确定心肌细胞中p21的调节，并进一步探索p21介导的对DOX心脏毒性的保护。核心假设是心肌p21水平决定了对DOX诱导的心肌细胞凋亡和心肌病的抵抗。我计划通过实现以下三个具体目标来测试中心假设：1）研究p21在心肌细胞中的表达和降解[指导]; 2）定义p21介导的对DOX心脏毒性的抵抗机制[独立]; 3）证明p21对DOX诱导的心肌病的保护作用[独立]。