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

项目总结： 心血管疾病是男性和女性的主要死亡原因，但在 心脏功能不全的表现。在心脏临床结果中观察到性别二型性，但 这些效应背后的分子机制在很大程度上是未知的。理解性知识的重要性 专注于内分泌干扰的环境研究进一步强调了心脏健康中的二相性 化学物质，如双酚类。通过接触消费品(每天)接触双酚。 和/或医疗器械。双酚A(BPA)是雌激素，心脏毒性可能是通过雌激素介导的 信号和钙的处理。需要进行实验工作来了解潜在的机制。 心血管性别差异，以及心肌对化学物质暴露的反应。数据来自 我们的实验室指出心脏生理学上的性别和区域组织差异，在 双酚暴露后的电生理和钙处理。使用体外创新的组合，例如 我们将在这些发现的基础上解决雌激素的中心假说 受体和离子通道的表达在内在性二态中起着关键作用，这种二态可以直接 由干扰内分泌的化学物质调节。目标1将综合评估性别差异 心脏电生理学和兴奋-收缩耦合，使用赞助商实验室的既定方法。 目的2研究异种雌激素(雌二醇、双酚A、双酚S、双酚F)对心脏的影响。 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-以及 可能会突出临床前安全测试和心脏药物治疗的新靶点。完成这项工作 提案还可以为在制造业中使用扰乱内分泌的化学品的监管决定提供信息 医疗器械的风险--考虑易受伤害的患者人群中双酚A暴露的增加。这项建议 包括一项为期三年的培训计划，该计划将支持我的科学成长，该计划建立在我的 赞助商(Posnack博士-心脏电生理学、内分泌干扰物)和共同赞助商(石桥博士- 自主神经/心血管临床前模型)。我还将受益于合作者的指导和 指导团队，他们将在职业发展、拟议目标的目标和实验方面提供指导 技术(例如，超声心动图、心内导管、质谱学蛋白质组学)。这项培训计划将 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 支持我未来独立领导一家转化型心血管研究实验室的目标。

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.