Sex-Specific Differences in the Development of Anthracycline Cardiotoxicity

项目总结 这项提案试图定义导致蒽环类药物性别差异的机制。 心脏毒性。该项目将由贝丝以色列女执事的医生兼研究员阿尔蒂·阿斯纳尼博士领导 他还是哈佛大学医学院(HMS)的讲师。基于她的化学反应 背景和临床专业知识，阿斯纳尼博士独一无二地很好地描述了生化 为了确定新的心脏保护策略，我们将继续研究导致蒽环类药物心脏毒性的途径。 Asnani博士于2017年应聘到BIDMC，目前担任BIDMC 心脏肿瘤学项目。在这个项目中，她将与罗伯特·格斯滕博士合作 BIDMC心血管内科和哈佛医学院医学教授。Gerszten博士已经 在基于质谱学的代谢组谱分析方面有丰富的经验，以揭示新的机制 心脏代谢疾病。他将担任阿斯纳尼博士项目的顾问，并监督群众 在她的提案中概述了光谱实验。用于对从BIDMC收集的数据进行统计分析 回顾心脏毒性患者登记，阿斯纳尼博士将专门与大四学生米歇尔·凯斯博士合作 Gerszten博士团队中的统计学家。凯斯博士在马丁·拉伦博士的指导下获得博士学位，马丁·拉伦博士 是弗雷明翰心脏研究的统计主任和波士顿大学的医学教授 医疗中心。Pier Paolo Pandolfi博士还将担任阿斯纳尼博士项目的合作者和顾问， 鉴于他在癌症生物学方面的丰富经验，以及利用小鼠模型开发抗肿瘤疗法。 他是BIDMC癌症中心和癌症研究所所长， BIDMC医学系遗传学，哈佛大学医学和病理学教授 医学院。在BIDMC，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，科学专业知识，以及 跨BIDMC、Longwood医疗区和HMS的协作机会。 在这项提案中，阿斯纳尼博士概述了一系列方法来阐明雌激素代谢在以下方面的作用 蒽环类药物心脏毒性中性二型性的潜在介体。使用慢性阻塞性肺疾病小鼠模型 阿霉素心肌病，她将确定如何调节细胞色素P450-1介导的雌二醇代谢 以性别特有的方式提供心脏保护。她还将调查特定性别的差异是如何 在这个模型中，线粒体的生物发生有助于心脏毒性的发展。最后，她将评估 雌激素代谢在BIDMC心脏毒性回顾登记中的作用，包括1954年 非雌激素依赖型肿瘤患者接受蒽环类药物治疗。如果成功，这条调查路线 可使心脏毒性风险较低的患者使用更高剂量和更有效的蒽环类药物 并最终促进新的心脏保护疗法的开发。

PROJECT SUMMARY This proposal seeks to define the mechanisms that contribute to sex-specific differences in anthracycline cardiotoxicity. The project will be led by Dr. Aarti Asnani, a physician-investigator at Beth Israel Deaconess Medical Center (BIDMC) and an Instructor at Harvard Medical School (HMS). Based on her chemistry background and clinical expertise, Dr. Asnani is uniquely well-positioned to characterize the biochemical pathways that contribute to anthracycline cardiotoxicity in order to identify new cardioprotective strategies. Dr. Asnani was recruited to BIDMC in 2017, where she currently serves as the Associate Director of the Cardio-Oncology Program. For this project, she will collaborate with Dr. Robert Gerszten, Chief of Cardiovascular Medicine at BIDMC and Professor of Medicine at Harvard Medical School. Dr. Gerszten has extensive experience in mass spectrometry-based metabolomic profiling to uncover new mechanisms of cardiometabolic disease. He will serve as an advisor for Dr. Asnani’s project and supervise the mass spectrometry experiments outlined in her proposal. For statistical analyses of data collected from the BIDMC retrospective cardiotoxicity patient registry, Dr. Asnani will work specifically with Michelle Keyes, PhD, a senior statistician in Dr. Gerszten’s group. Dr. Keyes received her PhD under the mentorship of Dr. Martin Laron, who is Director of Statistics for the Framingham Heart Study and Professor of Medicine at Boston University Medical Center. Dr. Pier Paolo Pandolfi will also serve as a collaborator and advisor for Dr. Asnani’s project, given his extensive experience in cancer biology and the use of mouse models to develop antitumor therapies. He is the Director of the BIDMC Cancer Center and Cancer Research Institute, Chief of the Division of Genetics in the BIDMC Department of Medicine, and a Professor of Medicine and Pathology at Harvard Medical School. At BIDMC, 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, the Longwood Medical Area, and HMS. In this proposal, Dr. Asnani has outlined a series of approaches to elucidate the role of estrogen metabolism as a potential mediator of sexual dimorphism in anthracycline cardiotoxicity. Using a mouse model of chronic doxorubicin cardiomyopathy, she will determine how modulation of CYP1-mediated estradiol metabolism confers cardioprotection in a sex-specific manner. She will also investigate how sex-specific differences in mitochondrial biogenesis contribute to the development of cardiotoxicity in this model. Finally, she will assess the role of estrogen metabolism in the BIDMC retrospective cardiotoxicity registry, which includes 1954 patients treated with anthracyclines for non-estrogen-dependent tumors. If successful, this line of investigation may enable the use of higher and more effective doses of anthracyclines in patients at low risk of cardiotoxicity and ultimately facilitate the development of new cardioprotective therapies.