Sex-Specific Differences in the Development of Anthracycline Cardiotoxicity

项目摘要 该提案旨在确定蒽环类抗生素性别特异性差异的机制 心脏毒性该项目将由Beth Israel Deaconess的医生兼研究员Aarti Asnani博士领导 医学中心（BIDMC）和哈佛医学院（HMS）的讲师。根据她的化学反应 背景和临床专业知识，Asnani博士是唯一的定位，以表征生化 研究蒽环类药物心脏毒性的途径，以确定新的心脏保护策略。 博士Asnani于2017年被招聘到BIDMC，目前担任副主任。 肿瘤学计划。在这个项目中，她将与罗伯特·格斯顿博士合作， BIDMC心血管医学和哈佛医学院医学教授。格斯顿博士 在基于质谱的代谢组学分析方面的丰富经验，以揭示 心脏代谢疾病他将担任Asnani博士项目的顾问， 光谱实验概述了她的建议。对于从BIDMC收集的数据的统计分析 回顾性心脏毒性患者登记，Asnani博士将专门与米歇尔凯斯，博士，一个高级 Gerszten博士团队的统计学家Keyes博士在Martin Laron博士的指导下获得博士学位， 是心脏病研究的统计主任和波士顿大学的医学教授 医学中心Pier Paolo Pandolfi博士还将担任Asnani博士项目的合作者和顾问， 鉴于他在癌症生物学和使用小鼠模型开发抗肿瘤疗法方面的丰富经验， 他是BIDMC癌症中心和癌症研究所的主任， BIDMC医学系遗传学教授，哈佛医学和病理学教授 医学院在BIDMC，Asnani博士受益于强大的机构支持和丰富的研究 环境她可以使用各种核心设施和设备，科学专业知识， 合作的机会，扩展到整个BIDMC，朗伍德医疗区，和HMS。 在这份提案中，Asnani博士概述了一系列方法来阐明雌激素代谢的作用， 蒽环类药物心脏毒性中两性异形的潜在介体。使用小鼠模型， 她将确定如何调节CYP1介导的雌二醇代谢， 以性别特异性方式提供心脏保护。她还将研究如何性别特异性差异， 线粒体生物发生有助于该模型中心脏毒性的发展。最后，她将评估 雌激素代谢在BIDMC回顾性心脏毒性登记中的作用，包括1954年 用蒽环类药物治疗非雌激素依赖性肿瘤的患者。如果成功的话，这条线索的调查 可以使在心脏毒性风险低的患者中使用更高和更有效剂量的蒽环类药物 并最终促进新的心脏保护疗法的发展。

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.