Promoting chemoresistance in the heart

项目简介(申请人提供)：危及生命的心肌病和心力衰竭是一系列化疗药物的常见副作用，例如蒽环类抗生素(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，也是化疗所致心脏毒性最常见的原因之一。因此，我选择在该方案中使用小鼠和原代心肌细胞来评估对DOX的化疗耐药性。DOX心脏毒性是由氧化应激和遗传毒性应激诱导的心肌细胞凋亡所致。因此，保护心肌组织免受细胞凋亡的影响是预防DOX所致心肌病的关键。虽然DOX的心脏毒性已经得到了广泛的研究，但成功的治疗策略仍然没有找到。我的导师琼·泰勒博士的实验室之前的工作已经确定，粘着斑激酶(FAK)是一种关键的保护分子，可以防止心脏中的心肌细胞凋亡。最近，我证明了FAK依赖的对DOX心脏毒性的保护是由细胞周期蛋白依赖性激酶(CDK)抑制物(CDKI)p21Cip1/WAF1(P21)介导的。以往关于包括p21在内的CDKI在心肌细胞中的研究主要集中在增殖和肥大上。在这里，我的结果支持了p21在调节心脏化疗耐药和细胞凋亡方面的新功能。作为这项工作的延伸，我的长期目标是建立CDKI在心肌细胞生存信号中的参与。为了实现这一目标，我的K99/R00应用程序的目的是确定p21在心肌细胞中的调节，并进一步探索p21介导的对DOX心脏毒性的保护作用。中心假设是，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检验中心假设：1)研究p21在心肌细胞中的表达和降解[被指导的]；2)确定p21介导的抵抗DOX心脏毒性的机制[独立]；以及3)证明p21对DOX诱导的心肌病[独立]的保护作用。

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].