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

研究心脏电功能和机械功能的性别差异以及环境异雌激素的影响

基本信息

批准号：
10626719
负责人：
Blake Leslie Cooper
金额：
$ 3.96万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-02 至 2024-01-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10626719
关键词：
Action Potentials Address Anti-Arrhythmia Agents Arrhythmia Biological Monitoring Calcium Calcium Signaling Cardiac Cardiac Electrophysiologic Techniques Cardiac Myocytes Cardiac Surgery procedures Cardiac health Cardiotoxicity Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Catheters Cause of Death Characteristics Chemical Exposure Chemicals Clinical Clinical Trials Coupling Data Decision Making Disease model Drug or Chemical Echocardiography Electrocardiogram Electrophysiology (science)Endocrine Disruptors Endocrine disruption Environmental Health Environmental Impact Equilibrium Estradiol Estrogen Receptors Estrogens Exposure to Female Functional disorder Future General Population Genomics Glean Goals Gonadal Steroid Hormones Growth Heart Heart Diseases Heart Rate Hormones Hypertension In Vitro Incidence Ion Channel Knowledge L-Type Calcium Channels Laboratory Research Longitudinal Studies Low Cardiac Output Maps Measurement Mechanics Mediating Medical Medical Device Mentors Methods Microelectrodes Molecular Myocardial Myocardial Stunning Myocardial dysfunction Myocardium Optics Outcome Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Physiology Play Population Postmenopause Potassium Channel Pre-Clinical Model Preclinical Testing Predisposition Premenopause Preparation Procedures Production Property Proteomics Protocols documentation Reperfusion Injury Reporting Research Project Grants Role Sampling Sex Differences Signal Transduction Technical Expertise Techniques Testing Tissues Toxicology Training Woman Work analog bisphenol A cardioprotection cardiovascular disorder risk cardiovascular health cardiovascular risk factor career development clinically relevant consumer product electrical property estrogenic experience exposed human population heart function in vivo innovation male manufacture mechanical properties men mortality neglect patient population polycarbonate plastic preclinical safety pressure research study response safety testing sex sexual dimorphism voltage xenoestrogen young woman

项目摘要

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.

项目概要：心血管疾病是男性和女性死亡的主要原因，但两者之间存在差异在心脏临床结果中观察到心脏功能障碍的表现，但这些影响背后的分子机制在很大程度上尚不清楚。了解性的重要性。以内分泌干扰为重点的环境研究进一步强调了心脏健康的二态性化学物质，例如双酚（每天）通过接触消费品而发生接触。双酚 A (BPA) 具有雌激素性，心脏毒性可能是通过雌激素介导的。需要进行实验工作来了解潜在的机制。心血管性别特异性差异，以及心肌对化学物质暴露的反应性数据。我们的实验室指出了心脏生理学中性别特异性和区域组织的差异，这对心脏生理学产生了显着的破坏双酚暴露后的电生理学和钙处理结合使用创新的体外实验。体内和体内方法，我们将根据这些发现来解决雌激素这一中心假设受体和离子通道表达在内在性别二态性中起着关键作用，这可以直接目标 1 将全面评估内分泌干扰化学物质的性别差异。使用申办者实验室的既定方法进行心脏电生理学和兴奋收缩耦合。目标 2 将研究异雌激素（雌二醇、双酚 A、双酚 S、双酚 F）对心脏检查的影响生理学，特别关注雌激素信号传导、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——并且可能会突出临床前安全性测试和心脏药物治疗的新目标。该提案还可以为有关在制造过程中使用内分泌干扰化学品的监管决策提供信息医疗设备——考虑到弱势患者群体中双酚 A 的暴露量增加。包括一个为期三年的培训计划，该计划将支持我的科学成长，该计划建立在我的专业知识的基础上发起人（Posnack 博士 – 心脏电生理学、内分泌干扰物）和共同发起人（Ishibashi 博士 – 自主/心血管临床前模型）我还将受益于合作者和专家的指导。指导团队，他们将在职业发展、拟议目标和实验方面提供指导本培训计划将涵盖超声心动图、心内导管、质谱蛋白质组学等技术。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转化心血管研究实验室的未来目标。