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

项目总结:

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.