Promoting chemoresistance in the heart

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（如阿霉素、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 药物和化疗诱导的心脏毒性的最众所周知的原因。所以我选择 使用小鼠和原代心肌细胞评估该提议中针对DOX的化学抗性。DOX 心脏毒性归因于氧化和遗传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是防止DOX诱导的心肌细胞凋亡的关键。 心肌病虽然DOX心脏毒性已被广泛研究，但成功的治疗策略 仍然无法使用。我的导师琼·泰勒博士的实验室以前的工作已经确定了 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 表明FAK依赖性保护DOX心脏毒性是由细胞周期蛋白依赖性的 激酶（CDK）抑制剂（CDKI）p21 Cip 1/WAF 1（p21）。先前关于CDKIs（包括p21）的研究 心肌细胞主要集中在增殖和肥大上。在这里，我的研究结果支持了一个新的 p21在心脏化疗耐药性和细胞凋亡调节中的作用作为这项工作的延伸，我 长期目标是确定CDKIs参与心肌细胞存活信号传导。努力实现这一目标 我的K99/R 00应用程序的目标是确定心肌细胞中p21的调节， 进一步探索p21介导的针对DOX心脏毒性的保护。核心假设是心肌 p21水平决定对DOX诱导的心肌细胞凋亡和心肌病的抵抗。我打算测试一下 通过完成以下三个具体目标来实现中心假设：1）研究表达和 p21在心肌细胞中的降解[指导]; 2）定义p21介导的DOX抗性机制 心脏毒性[独立];和3）证明p21对DOX诱导的心肌病的保护作用 [独立]。

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].