CYP1 Inhibition as a New Therapeutic Strategy for Doxorubicin Cardiomyopathy

项目摘要 该提案反映了Beth心脏病专家Aarti Asnani博士的五年职业发展计划 以色列女执事医疗中心（BIDMC）和哈佛医学院（HMS）讲师。阿斯纳尼医生 研究重点是蒽环类药物引起的心肌病，这是导致糖尿病发病率和死亡率的主要因素。 不断增长的癌症幸存者基于她的化学背景和临床专业知识， Asnani博士是独特的定位，以表征生化途径， 有助于化疗诱导的心脏毒性，以确定新的心脏保护疗法。 2017年，Asnani博士被招聘到BIDMC，担任肿瘤学副主任 程序. BIDMC的心血管内科主任Robert Gerszten博士一直非常关注BIDMC的心血管内科。 Asnani的职业发展自2006年以来，并将担任该项目的主要现场导师。博士 Gerszten在使用代谢物分析和蛋白质组学方面具有专业知识，可以识别 会导致心脏代谢疾病Asnani博士还将继续接受她的指导 博士后顾问Peterson博士的实验室于2017年1月搬到了犹他州大学。博士 彼得森是一位化学生物学专家，他率先将斑马鱼用于药物发现， 诱变两位导师都资金雄厚，长期以来一直指导成功的初级教育 教师。除了这种综合培训方法外，Asnani博士的科学咨询委员会还包括 世界级的科学家（MacRae、Liao、Pandolfi和Nebert博士）将在动物模型方面贡献专业知识 心肌病、癌细胞生物学和药理学的研究。Asnani博士受益于强大的机构支持 丰富的研究环境。她有机会获得广泛的核心设施和设备，科学 专业知识和合作机会，在BIDMC，朗伍德医疗区和HMS扩展。 在本申请中，Asnani博士概述了一系列实验，以阐明细胞色素P450的作用 家族1（CYP 1）酶作为阿霉素心脏毒性的新治疗靶点。在彼得森医生的工作 一个实验室发现小分子visnagin，一种CYP 1抑制剂，可以防止阿霉素诱导的 斑马鱼和小鼠的心肌病。在这项提案中，Asnani博士将使用转基因斑马鱼模型， 确定负责心脏毒性的特定CYP 1亚型。她将使用Cyp 1a 1/1a 2/1b 1（−/−）击倒 小鼠，以确定CYP 1酶的遗传抑制是否可以保护多柔比星心脏毒性。 哺乳动物模型最后，她将使用小鼠异种移植模型来确定CYP 1抑制对 阿霉素的抗肿瘤活性。通过完成拟议的项目，Asnani博士将补充她以前的 代谢物分析，化学生物学和斑马鱼模型的培训，以及转基因方面的额外培训 技术和小鼠模型。这些实验将成为独立调查的基础 该平台将寻求为化疗诱导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.