The Effects of Estrogen on Cardiac Arrhythmic Propensity

雌激素对心律失常倾向的影响

• 批准号: 10731400
• 负责人: Ilanit Itzhaki
• 金额: $ 24.83万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-10 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731400
• 关键词: Acute; Advisory Committees; Age; Anti-Arrhythmia Agents; Arrhythmia; Biological Assay; CRISPR/Cas technology; Calcium; Cardiac; Cardiology; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular system; Career Mobility; Cells; Clinical Research; Complement; Dangerousness; Databases; Development; Disease; Electrophysiology (science); Engineering; Estradiol; Estrogen Analogues; Estrogen Receptors; Estrogens; Female; Foundations; Future; Goals; Gonadal Steroid Hormones; Homeostasis; Hormones; Human; Hyperactivity; Image; Individual; Intention; Knowledge; Life; Long QT Syndrome; Maps; Mediating; Medicine; Mentors; Mentorship; Modeling; Modification; Molecular; Molecular Target; Myocardial tissue; Optics; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmacogenomics; Phase; Phenotype; Predisposition; Pregnancy; Process; Program Development; Research; Research Personnel; Research Project Grants; Resources; Risk Factors; RyR2; Screening procedure; Sex Differences; Structure; System; Technology; Therapeutic; Time; Tissues; Titrations; Torsades de Pointes; Training; Translational Research; Woman; Work; Youth; analog; calmodulin-dependent protein kinase II; cardiovascular health; career; career development; design; drug discovery; estrogenic; estrogenic activity; female sex hormone; genome editing; imaging approach; in silico; induced pluripotent stem cell derived cardiomyocytes; insight; knowledge base; male; meetings; men; monolayer; multi-electrode arrays; new therapeutic target; novel therapeutics; precision medicine; preservation; programs; reproductive; screening; sex; side effect; stem cell biology; stem cells; therapeutic target; translational impact; translational medicine; virtual screening

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. ! !

项目摘要 该提案描述了一个为期五年的职业发展计划，为Ilanit Itzhaki博士的职业生涯做好准备， 独立调查员这个项目将建立在Itzhaki博士作为干细胞生物学家的背景之上， 实验电生理学家通过提高她的知识基础，在性激素在心血管健康 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疗法的研究。Itzhaki博士将由Joseph Wu博士指导， 斯坦福大学心血管研究所所长。拟议的导师是干细胞生物学专家， 药物基因组学和利用iPSC衍生的心肌细胞（iPSC-CM）的药物发现。以补充 博士作为吴的导师，Itzhaki博士将与斯坦福大学妇女中心主任Marcia Stefanick博士共同指导 医学中心的性别差异，以及性激素和心血管健康领域的专家 和疾病Itzhaki博士培训的K99阶段将包括主要导师的结构化指导 和共同导师，与咨询委员会的补充会议，正式的课程，一个挑衅 研究项目和职业转型计划。对于症状性长QT综合征（LQTS）患者 容易危及生命的心律失常，怀孕可以促进一个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。解读反恐怖主义的贡献 雌激素可以导致急需的新的抗肿瘤治疗靶点的识别和设计， 新的治疗实体。在本提案的K99阶段，Itzhaki博士将评估雌激素对 在单细胞和多细胞中使用女性和男性LQT患者特异性iPSC-CM的发病倾向 水平（目标1）。然后，Itzhaki博士将确定促进雌激素抗肿瘤作用的细胞内机制靶点。 免疫益处（目标2）。已确定的有益抗肿瘤靶点将有助于指导Itzhaki博士在R 00 阶段，在雌激素类似物的设计中，将评估其持续的抗肿瘤益处 和没有心脏毒性（目标3），目的是提出新的治疗实体， 同时，他也是一个很好的医生。 所有年龄段的女性患者。总的来说，从伊扎克博士的建议中获得的见解可以有助于 显著地治疗LQTS患者，特别是易患先天性疾病的 患者，一般来说，并促进性别特异性治疗领域的不断发展。此外，使用iPSC-CM 作为一种“从盘子到床边”的方法，帮助设计抗疟疾治疗类似物， 一个高通量的类似物筛选平台，将大大有助于转化医学的前景。 最后，这项工作将为未来使用iPSC-CM作为人类患者的研究提供基础， 疾病特异性模型，询问性激素对心脏运动倾向的影响， 最终由伊扎基博士作为独立调查员进行。 ! !