Investigating sex-differences in cardiac electrical and mechanical function, and the impact of environmental xenoestrogens

项目摘要： 心血管疾病是男性和女性的主要死亡原因，但在死亡率方面存在差异。 心功能不全的表现。在心脏临床结局中观察到性别二态性，但 这些作用的分子机制在很大程度上是未知的。了解性的重要性 环境研究进一步强调了心脏健康的二型性， 化学品，如双酚。通过接触消费品发生双酚暴露（每日） 和/或医疗设备。双酚A（BPA）是雌激素，心脏毒性可能通过雌激素介导 信号传导和钙处理。需要进行实验工作以了解其背后的机制 心血管性别特异性差异以及心肌对化学品暴露的反应性。数据从 我们的实验室指出了心脏生理学中的性别特异性和区域组织差异， 双酚暴露后的电生理学和钙处理。使用创新的体外， 体内和体内方法，我们将建立在这些发现，以解决中心假设，雌激素 受体和离子通道表达在内在性二型中起着关键作用，这可以直接 受到内分泌干扰物的调节目标1将全面评估性别特异性差异 心脏电生理学和兴奋-收缩偶联，使用申办者实验室的既定方法。 目的2：研究外源性雌激素（雌二醇、双酚A、双酚S、双酚F）对大鼠心脏的影响， 生理学，特别关注雌激素信号，钙电流和细胞内钙处理。 这项研究的结果将广泛适用于心血管和环境健康领域， 可能为临床前安全性测试和心脏药物治疗提供新的靶点。完成本 该提案还可以为关于在制造过程中使用内分泌干扰化学品的监管决定提供信息。 医疗器械的风险-考虑到弱势患者人群中BPA暴露量的增加。这项建议 包括一个为期三年的培训计划，将支持我的科学成长，这是建立在我的专业知识， 申办者（Dr. Posnak-心脏电生理学、内分泌干扰物）和共同申办者（Dr. Ishibashi - 自主/心血管临床前模型）。我也将受益于合作者的指导和 指导团队，将提供职业发展指导，拟议目标的目标，以及实验 技术（例如，超声心动图、心内导管、质谱蛋白质组学）。本培训计划将 提高我在心血管生理学，毒理学和临床相关方法方面的知识-以及 支持我独立领导一个转化型心血管研究实验室的未来目标。

Project Summary: Cardiovascular disease is the leading cause of death for both men and women, yet there are differences in the manifestation of cardiac dysfunction. Sexual dimorphism is observed in cardiac clinical outcomes, but the molecular mechanisms underlying these effects are largely unknown. The importance of understanding sexual dimorphisms in cardiac health is further highlighted by environmental studies focused on endocrine-disrupting chemicals, such as bisphenols. Bisphenol exposure occurs (daily) through contact with consumer products and/or medical devices. Bisphenol A (BPA) is estrogenic and cardiotoxicity is likely mediated through estrogen signaling and calcium handling. Experimental work is needed to understand the mechanisms underlying cardiovascular sex-specific differences, as well as myocardial responsiveness to chemical exposures. Data from our lab points to sex-specific and regional tissue differences in cardiac physiology, with significant disruption in electrophysiology and calcium-handling after bisphenol exposure. Using a combination of innovative in vitro, ex vivo, and in vivo approaches, we will build upon these findings to address the central hypothesis that estrogen receptor and ion channel expression play a pivotal role in intrinsic sexual dimorphisms, which can be directly modulated by endocrine-disrupting chemicals. Aim 1 will comprehensively evaluate sex-specific differences in cardiac electrophysiology and excitation-contraction coupling, using established methods in the Sponsor’s lab. Aim 2 will investigate the impact of xenoestrogens (estradiol, bisphenol A, bisphenol S, bisphenol F) on cardiac physiology, with a particular focus on estrogen signaling, calcium current, and intracellular calcium handling. Results of this study will be broadly applicable to both the cardiovascular and environmental health fields – and may highlight new targets for preclinical safety testing and cardiac pharmacotherapies. Completion of this proposal can also inform regulatory decisions on the use of endocrine-disrupting chemicals in the manufacturing of medical devices – considering elevated BPA exposure in vulnerable patient populations. This proposal includes a three-year training plan that will support my scientific growth, which builds upon the expertise of my Sponsor (Dr. Posnack – cardiac electrophysiology, endocrine disruptors) and co-Sponsor (Dr. Ishibashi – autonomic/cardiovascular preclinical models). I will also benefit from the guidance of collaborators and a mentoring team, who will provide guidance in career development, goals of the proposed aims, and experimental techniques (e.g., echocardiography, intracardiac catheters, mass spec proteomics). This training proposal will advance my knowledge in cardiovascular physiology, toxicology, and clinically relevant approaches – and support my future goal of independently leading a translational cardiovascular research laboratory.