CYP1 Inhibition as a New Therapeutic Strategy for Doxorubicin Cardiomyopathy

项目总结 这项提议反映了贝思心脏病专家阿尔蒂·阿斯纳尼博士的五年职业发展计划 以色列女执事医学中心(BIDMC)和哈佛医学院(HMS)的讲师。阿斯纳尼医生的 研究重点是蒽环类药物引起的心肌病，这是#年发病率和死亡率的主要贡献者。 不断增长的癌症幸存者人数。根据她的化学背景和临床经验 心脏肿瘤学，阿斯纳尼博士独一无二地很好地描述了 促进化疗引起的心脏毒性，以确定新的心脏保护疗法。 2017年，Asnani博士被BIDMC聘用，担任心脏肿瘤科副主任 程序。BIDMC心血管内科主任Robert Gerszten博士一直非常参与Dr。 阿斯纳尼自2006年以来的职业发展，并将担任该项目的主要现场导师。Dr。 Gerszten在使用代谢物图谱和蛋白质组学来识别新的途径方面具有专业知识 会导致心脏代谢性疾病。阿斯纳尼博士还将继续接受她的指导 博士后导师彼得森博士，他的实验室于2017年1月搬到犹他大学。Dr。 彼得森是一位化学生物学专家，他开创了利用斑马鱼进行药物研发和 诱变。这两位导师都有充足的资金，并有长期指导成功少年的历史。 教职员工。除了这种综合培训方法，阿斯纳尼博士的科学咨询委员会还包括 世界级科学家(MacRae、Liao、Pandolfi和Nebert博士)，他们将贡献动物模型方面的专业知识 心肌病、癌细胞生物学和药理学。阿斯纳尼博士受益于强有力的机构支持 和丰富的研究环境。她可以使用广泛的核心设施和设备，科学的 跨BIDMC、Longwood医疗区和HMS的专业知识和协作机会。 在这一应用中，阿斯纳尼博士概述了一系列实验，以阐明细胞色素P450的作用 家族1(CYP1)酶作为阿霉素心脏毒性的新治疗靶点。彼得森博士之前的工作 实验室发现，小分子粘附素，一种细胞色素P4 1的抑制剂，可以预防阿霉素诱导的 斑马鱼和小鼠的心肌病。在这项提案中，阿斯纳尼博士将使用转基因斑马鱼模型来 确定导致心脏毒性的特定的CYP1亚型。她将使用Cyp1a1/1a2/1b1(−/−)基因敲除 小鼠建立CYP1酶的遗传抑制是否能保护小鼠免受阿霉素心脏毒性 哺乳动物模型。最后，她将使用小鼠异种移植模型来确定抑制细胞色素P4501对 阿霉素的抗肿瘤活性。通过完成提议的项目，阿斯纳尼博士将补充她之前的 代谢物分析、化学生物学和斑马鱼模型方面的培训，以及转基因培训 技术和鼠标模型。这些实验将构成独立调查的基础 该平台将寻求为化疗引起的心脏毒性患者开发新的治疗方法。

PROJECT SUMMARY This proposal reflects a five-year career development plan for Dr. Aarti Asnani, a staff cardiologist at Beth Israel Deaconess Medical Center (BIDMC) and an Instructor at Harvard Medical School (HMS). Dr. Asnani’s research focuses on anthracycline-induced cardiomyopathy, a major contributor to morbidity and mortality in the growing population of cancer survivors. Based on her chemistry background and clinical expertise in cardio-oncology, Dr. Asnani is uniquely well-positioned to characterize the biochemical pathways that contribute to chemotherapy-induced cardiotoxicity in order to identify new cardioprotective therapies. In 2017, Dr. Asnani was recruited to BIDMC where she serves as Associate Director of the Cardio-Oncology Program. Dr. Robert Gerszten, Chief of Cardiovascular Medicine at BIDMC, has been very involved in Dr. Asnani’s career development since 2006 and will serve as the primary on-site mentor for this project. Dr. Gerszten has expertise in the use of metabolite profiling and proteomics to identify new pathways that contribute to cardiometabolic disease. Dr. Asnani will also continue to receive mentorship from her postdoctoral advisor, Dr. Peterson, whose laboratory moved to the University of Utah in January 2017. Dr. Peterson is an expert in chemical biology and has pioneered the use of zebrafish for drug discovery and mutagenesis. Both preceptors are well-funded and have a longstanding history of mentoring successful junior faculty. In addition to this combined training approach, Dr. Asnani’s Scientific Advisory Committee consists of world-class scientists (Drs. MacRae, Liao, Pandolfi, and Nebert) who will contribute expertise in animal models of cardiomyopathy, cancer cell biology, and pharmacology. Dr. Asnani benefits from strong institutional support and a rich research environment. She has access to a broad range of core facilities and equipment, scientific expertise, and opportunities for collaboration that extend across BIDMC, Longwood Medical Area, and HMS. In this application, Dr. Asnani has outlined a series of experiments to elucidate the role of Cytochrome P450 family 1 (CYP1) enzymes as new therapeutic targets for doxorubicin cardiotoxicity. Prior work in Dr. Peterson’s lab identified the small molecule visnagin, a CYP1 inhibitor, as protecting against doxorubicin-induced cardiomyopathy in zebrafish and mice. In this proposal, Dr. Asnani will use transgenic zebrafish models to identify the specific CYP1 isoform responsible for cardiotoxicity. She will use Cyp1a1/1a2/1b1(−/−) knockout mice to establish whether genetic inhibition of CYP1 enzymes protects against doxorubicin cardiotoxicity in a mammalian model. Finally, she will use a mouse xenograft model to determine the effect of CYP1 inhibition on doxorubicin’s anti-tumor activity. By completing the proposed project, Dr. Asnani will complement her prior training in metabolite profiling, chemical biology, and zebrafish models with additional training in transgenic techniques and mouse models. These experiments will form the basis for an independent investigative platform that will seek to develop new treatments for patients with chemotherapy-induced cardiotoxicity.