The Effects of Estrogen on Cardiac Arrhythmic Propensity

项目总结 这份提案描述了一项为期五年的职业发展计划，为伊扎基博士的职业生涯做好准备。 独立调查员。该项目将建立在伊扎基博士作为干细胞生物学家的背景之上，并 增强性激素在心血管健康中的知识基础的实验电生理学家 并提供她在分子心脏病学和药物化学方面的专业知识 药物发现和性别特异性治疗方面的研究。伊扎基博士将由约瑟夫·吴博士指导， 斯坦福大学心血管研究所所长。被提名的导师是干细胞生物学方面的专家， 药物基因组学，以及利用IPSC来源的心肌细胞(IPSC-CMS)的药物发现。来补充 吴博士的导师伊扎基博士将由斯坦福大学妇女中心主任Marcia Stefan ick博士共同指导 和医学中心的性别差异，性激素和心血管健康领域的专家 和疾病。Itzhaki博士K99阶段的培训将包括由初级导师进行有组织的指导 和共同导师，与咨询委员会的补充会议，正式的课程作业，具有挑衅性 研究项目，以及职业转型计划。对于有症状的长QT综合征(LQTS)患者 容易发生危及生命的心律失常，怀孕可以促进独特的抗心律失常时期 保护，当雌激素水平处于最高水平时。破译丹参的抗心律失常作用 雌激素可以导致急需的新的抗心律失常治疗靶点的确定和设计 新的治疗实体。在这项提案的K99阶段，伊扎基博士将评估雌激素对 单细胞和多细胞LQT患者特异性IPSC-CMS的心律失常倾向 级别(目标1)。然后，伊扎基博士将确定细胞内的机械性靶点，以促进雌激素的抗 心律失常益处(目标2)。识别出的有益的抗心律失常靶点，将有助于指导伊扎基博士在R00 雌激素类似物的设计阶段，将评估其持续的抗心律失常益处 和无心脏毒性(目标3)，目的是提出新的治疗实体， 优点基于荷尔蒙的抗心律失常的好处，但同时又允许治疗两种男性 以及各个年龄段的女性患者。总的来说，从伊扎基博士的提案中获得的见解可以帮助 对LQTS患者的治疗意义重大，尤其是易发生心律失常的先天性疾病 一般说来，患者促进了日益增长的性别特异性治疗领域。此外，使用IPSC-CMS 作为一种“从盘子到床边”的方法，帮助设计抗心律失常的治疗类似物，并作为 一个高通量的模拟筛选平台，将极大地促进转化医学的前景。 最后，这项工作将为未来使用IPSC-CMS作为以人为基础的患者-和 疾病特异性模型，询问性激素对心律失常倾向的影响， 最终由伊扎基博士作为独立调查员进行。 好了！ 好了！

PROJECT SUMMARY This proposal describes a five-year career development program to prepare Dr. Ilanit Itzhaki for a career as an independent investigator. This program will build on Dr. Itzhaki's background as a stem cell biologist and experimental electrophysiologist by enhancing her knowledge base in sex hormones in cardiovascular health and disease and providing her expertise in molecular cardiology and medicinal chemistry for translational research in drug discovery and sex-specific therapeutics. Dr. Itzhaki will be mentored by Dr. Joseph Wu, Director of the Stanford Cardiovascular Institute. The proposed mentor is an expert in stem cell biology, pharmacogenomics, and drug discovery utilizing iPSC-derived cardiomyocytes (iPSC-CMs). To complement Dr. Wu's mentorship, Dr. Itzhaki will be co-mentored by Dr. Marcia Stefanick, Director of the Stanford Women & Sex Differences in Medicine Center, and an expert in the field of sex hormones and cardiovascular health and disease. The K99 phase of Dr. Itzhaki's training will consist of structured mentorship by the primary mentor and co-mentor, complementary meetings with the advisory committee, formal coursework, a provocative research project, and a program for career transition. For symptomatic long QT syndrome (LQTS) patients prone to life threatening cardiac arrhythmia, pregnancy can facilitate a unique period of anti-arrhythmic protection, when estrogen hormone level is at its highest. Deciphering the anti-arrhythmic contribution of estrogen can lead to the identification of much-needed new anti-arrhythmic therapeutic targets and the design of novel therapeutic entities. In the K99 phase of this proposal, Dr. Itzhaki will assess the effect of estrogen on arrhythmic propensity using female and male LQT patient-specific iPSC-CMs at the single cell and multicellular levels (Aim 1). Dr. Itzhaki will then identify mechanistic intracellular targets that facilitate estrogen's anti- arrhythmic benefit (Aim 2). The identified beneficial antiarrhythmic targets, will help guide Dr. Itzhaki in the R00 phase, in the design of an estrogen analogue, which will be assessed for sustained anti-arrhythmic benefits and absence of cardiotoxicity (Aim 3), with the intention of proposing new therapeutic entities that take advantage of hormone-based anti-arrhythmic benefits, yet at the same time allow the treatment of both male and female patients at all ages. Collectively, the insights acquired from Dr. Itzhaki's proposal can contribute significantly to the treatment of LQTS patients, specifically, and arrhythmia-susceptible congenital disease patients, in general, and promote the growing field of sex-specific therapeutics. Furthermore, using iPSC-CMs as a "dish-to-bedside" approach, to aid in the design of anti-arrhythmic therapeutic analogues and to serve as a high-throughput analogue-screening platform, will greatly contribute to the prospect of translational medicine. Finally, this work will provide a foundation for future studies using iPSC-CMs, as a human based patient- and disease-specific model, to interrogate the effect of sex hormones on cardiac arrhythmic propensity, to be eventually carried out by Dr. Itzhaki as an independent investigator. ! !